Force transduction by cadherin adhesions in morphogenesis

Force transduction by cadherin adhesions in... | F1000Research "use strict";function _typeof(t){return(_typeof="function"==typeof Symbol&&"symbol"==typeof Symbol.iterator?function(t){return typeof t}:function(t){return t&&"function"==typeof Symbol&&t.constructor===Symbol&&t!==Symbol.prototype?"symbol":typeof t})(t)}!function(){var t=function(){var t,e,o=[],n=window,r=n;for(;r;){try{if(r.frames.__tcfapiLocator){t=r;break}}catch(t){}if(r===n.top)break;r=r.parent}t||(!function t(){var e=n.document,o=!!n.frames.__tcfapiLocator;if(!o)if(e.body){var r=e.createElement("iframe");r.style.cssText="display:none",r.name="__tcfapiLocator",e.body.appendChild(r)}else setTimeout(t,5);return!o}(),n.__tcfapi=function(){for(var t=arguments.length,n=new Array(t),r=0;r 3&&2===parseInt(n[1],10)&&"boolean"==typeof n[3]&&(e=n[3],"function"==typeof n[2]&&n[2]("set",!0)):"ping"===n[0]?"function"==typeof n[2]&&n[2]({gdprApplies:e,cmpLoaded:!1,cmpStatus:"stub"}):o.push(n)},n.addEventListener("message",(function(t){var e="string"==typeof t.data,o={};if(e)try{o=JSON.parse(t.data)}catch(t){}else o=t.data;var n="object"===_typeof(o)&&null!==o?o.__tcfapiCall:null;n&&window.__tcfapi(n.command,n.version,(function(o,r){var a={__tcfapiReturn:{returnValue:o,success:r,callId:n.callId}};t&&t.source&&t.source.postMessage&&t.source.postMessage(e?JSON.stringify(a):a,"*")}),n.parameter)}),!1))};"undefined"!=typeof module?module.exports=t:t()}(); dataLayer = dataLayer || []; // Standard GTM initialization - Google Consent Mode handles consent automatically (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= 'https://www.googletagmanager.com/gtm.js?id='+i+dl+ '>m_auth=hzk0Vc3qFsQYhCrIoHz68A>m_preview=env-1>m_cookies_win=x';f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer','GTM-MWFK8L5J'); ;window.NREUM||(NREUM={});NREUM.init={distributed_tracing:{enabled:true},privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]}}; ;NREUM.loader_config={accountID:"438030",trustKey:"438030",agentID:"772317073",licenseKey:"97f8f67f26",applicationID:"772317073"} ;NREUM.info={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net",licenseKey:"97f8f67f26",applicationID:"772317073",sa:1} ;/*! For license information please see nr-loader-spa-1.236.0.min.js.LICENSE.txt */ (()=>{"use strict";var e,t,r={5763:(e,t,r)=>{r.d(t,{P_:()=>l,Mt:()=>g,C5:()=>s,DL:()=>v,OP:()=>T,lF:()=>D,Yu:()=>y,Dg:()=>h,CX:()=>c,GE:()=>b,sU:()=>_});var n=r(8632),i=r(9567);const o={beacon:n.ce.beacon,errorBeacon:n.ce.errorBeacon,licenseKey:void 0,applicationID:void 0,sa:void 0,queueTime:void 0,applicationTime:void 0,ttGuid:void 0,user:void 0,account:void 0,product:void 0,extra:void 0,jsAttributes:{},userAttributes:void 0,atts:void 0,transactionName:void 0,tNamePlain:void 0},a={};function s(e){if(!e)throw new Error("All info objects require an agent identifier!");if(!a[e])throw new Error("Info for ".concat(e," was never set"));return a[e]}function c(e,t){if(!e)throw new Error("All info objects require an agent identifier!");a[e]=(0,i.D)(t,o),(0,n.Qy)(e,a[e],"info")}var u=r(7056);const d=()=>{const e={blockSelector:"[data-nr-block]",maskInputOptions:{password:!0}};return{allow_bfcache:!0,privacy:{cookies_enabled:!0},ajax:{deny_list:void 0,enabled:!0,harvestTimeSeconds:10},distributed_tracing:{enabled:void 0,exclude_newrelic_header:void 0,cors_use_newrelic_header:void 0,cors_use_tracecontext_headers:void 0,allowed_origins:void 0},session:{domain:void 0,expiresMs:u.oD,inactiveMs:u.Hb},ssl:void 0,obfuscate:void 0,jserrors:{enabled:!0,harvestTimeSeconds:10},metrics:{enabled:!0},page_action:{enabled:!0,harvestTimeSeconds:30},page_view_event:{enabled:!0},page_view_timing:{enabled:!0,harvestTimeSeconds:30,long_task:!1},session_trace:{enabled:!0,harvestTimeSeconds:10},harvest:{tooManyRequestsDelay:60},session_replay:{enabled:!1,harvestTimeSeconds:60,sampleRate:.1,errorSampleRate:.1,maskTextSelector:"*",maskAllInputs:!0,get blockClass(){return"nr-block"},get ignoreClass(){return"nr-ignore"},get maskTextClass(){return"nr-mask"},get blockSelector(){return e.blockSelector},set blockSelector(t){e.blockSelector+=",".concat(t)},get maskInputOptions(){return e.maskInputOptions},set maskInputOptions(t){e.maskInputOptions={...t,password:!0}}},spa:{enabled:!0,harvestTimeSeconds:10}}},f={};function l(e){if(!e)throw new Error("All configuration objects require an agent identifier!");if(!f[e])throw new Error("Configuration for ".concat(e," was never set"));return f[e]}function h(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");f[e]=(0,i.D)(t,d()),(0,n.Qy)(e,f[e],"config")}function g(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");var r=l(e);if(r){for(var n=t.split("."),i=0;i {r.d(t,{D:()=>i});var n=r(50);function i(e,t){try{if(!e||"object"!=typeof e)return(0,n.Z)("Setting a Configurable requires an object as input");if(!t||"object"!=typeof t)return(0,n.Z)("Setting a Configurable requires a model to set its initial properties");const r=Object.create(Object.getPrototypeOf(t),Object.getOwnPropertyDescriptors(t)),o=0===Object.keys(r).length?e:r;for(let a in o)if(void 0!==e[a])try{"object"==typeof e[a]&&"object"==typeof t[a]?r[a]=i(e[a],t[a]):r[a]=e[a]}catch(e){(0,n.Z)("An error occurred while setting a property of a Configurable",e)}return r}catch(e){(0,n.Z)("An error occured while setting a Configurable",e)}}},6818:(e,t,r)=>{r.d(t,{Re:()=>i,gF:()=>o,q4:()=>n});const n="1.236.0",i="PROD",o="CDN"},385:(e,t,r)=>{r.d(t,{FN:()=>a,IF:()=>u,Nk:()=>f,Tt:()=>s,_A:()=>o,il:()=>n,pL:()=>c,v6:()=>i,w1:()=>d});const n="undefined"!=typeof window&&!!window.document,i="undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self.navigator instanceof WorkerNavigator||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis.navigator instanceof WorkerNavigator),o=n?window:"undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis),a=""+o?.location,s=/iPad|iPhone|iPod/.test(navigator.userAgent),c=s&&"undefined"==typeof SharedWorker,u=(()=>{const e=navigator.userAgent.match(/Firefox[/\s](\d+\.\d+)/);return Array.isArray(e)&&e.length>=2?+e[1]:0})(),d=Boolean(n&&window.document.documentMode),f=!!navigator.sendBeacon},1117:(e,t,r)=>{r.d(t,{w:()=>o});var n=r(50);const i={agentIdentifier:"",ee:void 0};class o{constructor(e){try{if("object"!=typeof e)return(0,n.Z)("shared context requires an object as input");this.sharedContext={},Object.assign(this.sharedContext,i),Object.entries(e).forEach((e=>{let[t,r]=e;Object.keys(i).includes(t)&&(this.sharedContext[t]=r)}))}catch(e){(0,n.Z)("An error occured while setting SharedContext",e)}}}},8e3:(e,t,r)=>{r.d(t,{L:()=>d,R:()=>c});var n=r(2177),i=r(1284),o=r(4322),a=r(3325);const s={};function c(e,t){const r={staged:!1,priority:a.p[t]||0};u(e),s[e].get(t)||s[e].set(t,r)}function u(e){e&&(s[e]||(s[e]=new Map))}function d(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:"",t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:"feature";if(u(e),!e||!s[e].get(t))return a(t);s[e].get(t).staged=!0;const r=[...s[e]];function a(t){const r=e?n.ee.get(e):n.ee,a=o.X.handlers;if(r.backlog&&a){var s=r.backlog[t],c=a[t];if(c){for(var u=0;s&&u {let[t,r]=e;return r.staged}))&&(r.sort(((e,t)=>e[1].priority-t[1].priority)),r.forEach((e=>{let[t]=e;a(t)})))}function f(e,t){var r=e[1];(0,i.D)(t[r],(function(t,r){var n=e[0];if(r[0]===n){var i=r[1],o=e[3],a=e[2];i.apply(o,a)}}))}},2177:(e,t,r)=>{r.d(t,{c:()=>f,ee:()=>u});var n=r(8632),i=r(2210),o=r(1284),a=r(5763),s="nr@context";let c=(0,n.fP)();var u;function d(){}function f(e){return(0,i.X)(e,s,l)}function l(){return new d}function h(){u.aborted=!0,u.backlog={}}c.ee?u=c.ee:(u=function e(t,r){var n={},c={},f={},g=!1;try{g=16===r.length&&(0,a.OP)(r).isolatedBacklog}catch(e){}var p={on:b,addEventListener:b,removeEventListener:y,emit:v,get:x,listeners:w,context:m,buffer:A,abort:h,aborted:!1,isBuffering:E,debugId:r,backlog:g?{}:t&&"object"==typeof t.backlog?t.backlog:{}};return p;function m(e){return e&&e instanceof d?e:e?(0,i.X)(e,s,l):l()}function v(e,r,n,i,o){if(!1!==o&&(o=!0),!u.aborted||i){t&&o&&t.emit(e,r,n);for(var a=m(n),s=w(e),d=s.length,f=0;fn,p:()=>i});var n=r(2177).ee.get("handle");function i(e,t,r,i,o){o?(o.buffer([e],i),o.emit(e,t,r)):(n.buffer([e],i),n.emit(e,t,r))}},4322:(e,t,r)=>{r.d(t,{X:()=>o});var n=r(5546);o.on=a;var i=o.handlers={};function o(e,t,r,o){a(o||n.E,i,e,t,r)}function a(e,t,r,i,o){o||(o="feature"),e||(e=n.E);var a=t[o]=t[o]||{};(a[r]=a[r]||[]).push([e,i])}},3239:(e,t,r)=>{r.d(t,{bP:()=>s,iz:()=>c,m$:()=>a});var n=r(385);let i=!1,o=!1;try{const e={get passive(){return i=!0,!1},get signal(){return o=!0,!1}};n._A.addEventListener("test",null,e),n._A.removeEventListener("test",null,e)}catch(e){}function a(e,t){return i||o?{capture:!!e,passive:i,signal:t}:!!e}function s(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;window.addEventListener(e,t,a(r,n))}function c(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;document.addEventListener(e,t,a(r,n))}},4402:(e,t,r)=>{r.d(t,{Ht:()=>u,M:()=>c,Rl:()=>a,ky:()=>s});var n=r(385);const i="xxxxxxxx-xxxx-4xxx-yxxx-xxxxxxxxxxxx";function o(e,t){return e?15&e[t]:16*Math.random()|0}function a(){const e=n._A?.crypto||n._A?.msCrypto;let t,r=0;return e&&e.getRandomValues&&(t=e.getRandomValues(new Uint8Array(31))),i.split("").map((e=>"x"===e?o(t,++r).toString(16):"y"===e?(3&o()|8).toString(16):e)).join("")}function s(e){const t=n._A?.crypto||n._A?.msCrypto;let r,i=0;t&&t.getRandomValues&&(r=t.getRandomValues(new Uint8Array(31)));const a=[];for(var s=0;s {r.d(t,{Bq:()=>n,Hb:()=>o,oD:()=>i});const n="NRBA",i=144e5,o=18e5},7894:(e,t,r)=>{function n(){return Math.round(performance.now())}r.d(t,{z:()=>n})},7243:(e,t,r)=>{r.d(t,{e:()=>o});var n=r(385),i={};function o(e){if(e in i)return i[e];if(0===(e||"").indexOf("data:"))return{protocol:"data"};let t;var r=n._A?.location,o={};if(n.il)t=document.createElement("a"),t.href=e;else try{t=new URL(e,r.href)}catch(e){return o}o.port=t.port;var a=t.href.split("://");!o.port&&a[1]&&(o.port=a[1].split("/")[0].split("@").pop().split(":")[1]),o.port&&"0"!==o.port||(o.port="https"===a[0]?"443":"80"),o.hostname=t.hostname||r.hostname,o.pathname=t.pathname,o.protocol=a[0],"/"!==o.pathname.charAt(0)&&(o.pathname="/"+o.pathname);var s=!t.protocol||":"===t.protocol||t.protocol===r.protocol,c=t.hostname===r.hostname&&t.port===r.port;return o.sameOrigin=s&&(!t.hostname||c),"/"===o.pathname&&(i[e]=o),o}},50:(e,t,r)=>{function n(e,t){"function"==typeof console.warn&&(console.warn("New Relic: ".concat(e)),t&&console.warn(t))}r.d(t,{Z:()=>n})},2587:(e,t,r)=>{r.d(t,{N:()=>c,T:()=>u});var n=r(2177),i=r(5546),o=r(8e3),a=r(3325);const s={stn:[a.D.sessionTrace],err:[a.D.jserrors,a.D.metrics],ins:[a.D.pageAction],spa:[a.D.spa],sr:[a.D.sessionReplay,a.D.sessionTrace]};function c(e,t){const r=n.ee.get(t);e&&"object"==typeof e&&(Object.entries(e).forEach((e=>{let[t,n]=e;void 0===u[t]&&(s[t]?s[t].forEach((e=>{n?(0,i.p)("feat-"+t,[],void 0,e,r):(0,i.p)("block-"+t,[],void 0,e,r),(0,i.p)("rumresp-"+t,[Boolean(n)],void 0,e,r)})):n&&(0,i.p)("feat-"+t,[],void 0,void 0,r),u[t]=Boolean(n))})),Object.keys(s).forEach((e=>{void 0===u[e]&&(s[e]?.forEach((t=>(0,i.p)("rumresp-"+e,[!1],void 0,t,r))),u[e]=!1)})),(0,o.L)(t,a.D.pageViewEvent))}const u={}},2210:(e,t,r)=>{r.d(t,{X:()=>i});var n=Object.prototype.hasOwnProperty;function i(e,t,r){if(n.call(e,t))return e[t];var i=r();if(Object.defineProperty&&Object.keys)try{return Object.defineProperty(e,t,{value:i,writable:!0,enumerable:!1}),i}catch(e){}return e[t]=i,i}},1284:(e,t,r)=>{r.d(t,{D:()=>n});const n=(e,t)=>Object.entries(e||{}).map((e=>{let[r,n]=e;return t(r,n)}))},4351:(e,t,r)=>{r.d(t,{P:()=>o});var n=r(2177);const i=()=>{const e=new WeakSet;return(t,r)=>{if("object"==typeof r&&null!==r){if(e.has(r))return;e.add(r)}return r}};function o(e){try{return JSON.stringify(e,i())}catch(e){try{n.ee.emit("internal-error",[e])}catch(e){}}}},3960:(e,t,r)=>{r.d(t,{K:()=>a,b:()=>o});var n=r(3239);function i(){return"undefined"==typeof document||"complete"===document.readyState}function o(e,t){if(i())return e();(0,n.bP)("load",e,t)}function a(e){if(i())return e();(0,n.iz)("DOMContentLoaded",e)}},8632:(e,t,r)=>{r.d(t,{EZ:()=>u,Qy:()=>c,ce:()=>o,fP:()=>a,gG:()=>d,mF:()=>s});var n=r(7894),i=r(385);const o={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net"};function a(){return i._A.NREUM||(i._A.NREUM={}),void 0===i._A.newrelic&&(i._A.newrelic=i._A.NREUM),i._A.NREUM}function s(){let e=a();return e.o||(e.o={ST:i._A.setTimeout,SI:i._A.setImmediate,CT:i._A.clearTimeout,XHR:i._A.XMLHttpRequest,REQ:i._A.Request,EV:i._A.Event,PR:i._A.Promise,MO:i._A.MutationObserver,FETCH:i._A.fetch}),e}function c(e,t,r){let i=a();const o=i.initializedAgents||{},s=o[e]||{};return Object.keys(s).length||(s.initializedAt={ms:(0,n.z)(),date:new Date}),i.initializedAgents={...o,[e]:{...s,[r]:t}},i}function u(e,t){a()[e]=t}function d(){return function(){let e=a();const t=e.info||{};e.info={beacon:o.beacon,errorBeacon:o.errorBeacon,...t}}(),function(){let e=a();const t=e.init||{};e.init={...t}}(),s(),function(){let e=a();const t=e.loader_config||{};e.loader_config={...t}}(),a()}},7956:(e,t,r)=>{r.d(t,{N:()=>i});var n=r(3239);function i(e){let t=arguments.length>1&&void 0!==arguments[1]&&arguments[1],r=arguments.length>2?arguments[2]:void 0,i=arguments.length>3?arguments[3]:void 0;return void(0,n.iz)("visibilitychange",(function(){if(t)return void("hidden"==document.visibilityState&&e());e(document.visibilityState)}),r,i)}},1214:(e,t,r)=>{r.d(t,{em:()=>v,u5:()=>N,QU:()=>S,_L:()=>I,Gm:()=>L,Lg:()=>M,gy:()=>U,BV:()=>Q,Kf:()=>ee});var n=r(2177);const i="nr@original";var o=Object.prototype.hasOwnProperty,a=!1;function s(e,t){return e||(e=n.ee),r.inPlace=function(e,t,n,i,o){n||(n="");var a,s,c,u="-"===n.charAt(0);for(c=0;c 2?n-2:0),o=2;o {r(A[T],e,w),r(E[T],e,w)})),r(l._A,"fetch",y),t.on(y+"end",(function(e,r){var n=this;if(r){var i=r.headers.get("content-length");null!==i&&(n.rxSize=i),t.emit(y+"done",[null,r],n)}else t.emit(y+"done",[e],n)})),t}const O={},j=["pushState","replaceState"];function S(e){const t=function(e){return(e||n.ee).get("history")}(e);return!l.il||O[t.debugId]++||(O[t.debugId]=1,s(t).inPlace(window.history,j,"-")),t}var P=r(3239);const C={},R=["appendChild","insertBefore","replaceChild"];function I(e){const t=function(e){return(e||n.ee).get("jsonp")}(e);if(!l.il||C[t.debugId])return t;C[t.debugId]=!0;var r=s(t),i=/[?&](?:callback|cb)=([^&#]+)/,o=/(.*)\.([^.]+)/,a=/^(\w+)(\.|$)(.*)$/;function c(e,t){var r=e.match(a),n=r[1],i=r[3];return i?c(i,t[n]):t[n]}return r.inPlace(Node.prototype,R,"dom-"),t.on("dom-start",(function(e){!function(e){if(!e||"string"!=typeof e.nodeName||"script"!==e.nodeName.toLowerCase())return;if("function"!=typeof e.addEventListener)return;var n=(a=e.src,s=a.match(i),s?s[1]:null);var a,s;if(!n)return;var u=function(e){var t=e.match(o);if(t&&t.length>=3)return{key:t[2],parent:c(t[1],window)};return{key:e,parent:window}}(n);if("function"!=typeof u.parent[u.key])return;var d={};function f(){t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}function l(){t.emit("jsonp-error",[],d),t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}r.inPlace(u.parent,[u.key],"cb-",d),e.addEventListener("load",f,(0,P.m$)(!1)),e.addEventListener("error",l,(0,P.m$)(!1)),t.emit("new-jsonp",[e.src],d)}(e[0])})),t}var k=r(5763);const H={};function L(e){const t=function(e){return(e||n.ee).get("mutation")}(e);if(!l.il||H[t.debugId])return t;H[t.debugId]=!0;var r=s(t),i=k.Yu.MO;return i&&(window.MutationObserver=function(e){return this instanceof i?new i(r(e,"fn-")):i.apply(this,arguments)},MutationObserver.prototype=i.prototype),t}const z={};function M(e){const t=function(e){return(e||n.ee).get("promise")}(e);if(z[t.debugId])return t;z[t.debugId]=!0;var r=n.c,o=s(t),a=k.Yu.PR;return a&&function(){function e(r){var n=t.context(),i=o(r,"executor-",n,null,!1);const s=Reflect.construct(a,[i],e);return t.context(s).getCtx=function(){return n},s}l._A.Promise=e,Object.defineProperty(e,"name",{value:"Promise"}),e.toString=function(){return a.toString()},Object.setPrototypeOf(e,a),["all","race"].forEach((function(r){const n=a[r];e[r]=function(e){let i=!1;[...e||[]].forEach((e=>{this.resolve(e).then(a("all"===r),a(!1))}));const o=n.apply(this,arguments);return o;function a(e){return function(){t.emit("propagate",[null,!i],o,!1,!1),i=i||!e}}}})),["resolve","reject"].forEach((function(r){const n=a[r];e[r]=function(e){const r=n.apply(this,arguments);return e!==r&&t.emit("propagate",[e,!0],r,!1,!1),r}})),e.prototype=a.prototype;const n=a.prototype.then;a.prototype.then=function(){var e=this,i=r(e);i.promise=e;for(var a=arguments.length,s=new Array(a),c=0;c e())),t};function m(e,t){i.inPlace(t,["onreadystatechange"],"fn-",E)}function b(){var e=this,t=r.context(e);e.readyState>3&&!t.resolved&&(t.resolved=!0,r.emit("xhr-resolved",[],e)),i.inPlace(e,f,"fn-",E)}if(function(e,t){for(var r in e)t[r]=e[r]}(o,p),p.prototype=o.prototype,i.inPlace(p.prototype,J,"-xhr-",E),r.on("send-xhr-start",(function(e,t){m(e,t),function(e){h.push(e),a&&(y?y.then(A):u?u(A):(w=-w,x.data=w))}(t)})),r.on("open-xhr-start",m),a){var y=c&&c.resolve();if(!u&&!c){var w=1,x=document.createTextNode(w);new a(A).observe(x,{characterData:!0})}}else t.on("fn-end",(function(e){e[0]&&e[0].type===d||A()}));function A(){for(var e=0;e {r.d(t,{t:()=>n});const n=r(3325).D.ajax},6660:(e,t,r)=>{r.d(t,{A:()=>i,t:()=>n});const n=r(3325).D.jserrors,i="nr@seenError"},3081:(e,t,r)=>{r.d(t,{gF:()=>o,mY:()=>i,t9:()=>n,vz:()=>s,xS:()=>a});const n=r(3325).D.metrics,i="sm",o="cm",a="storeSupportabilityMetrics",s="storeEventMetrics"},4649:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageAction},7633:(e,t,r)=>{r.d(t,{Dz:()=>i,OJ:()=>a,qw:()=>o,t9:()=>n});const n=r(3325).D.pageViewEvent,i="firstbyte",o="domcontent",a="windowload"},9251:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageViewTiming},3614:(e,t,r)=>{r.d(t,{BST_RESOURCE:()=>i,END:()=>s,FEATURE_NAME:()=>n,FN_END:()=>u,FN_START:()=>c,PUSH_STATE:()=>d,RESOURCE:()=>o,START:()=>a});const n=r(3325).D.sessionTrace,i="bstResource",o="resource",a="-start",s="-end",c="fn"+a,u="fn"+s,d="pushState"},7836:(e,t,r)=>{r.d(t,{BODY:()=>A,CB_END:()=>E,CB_START:()=>u,END:()=>x,FEATURE_NAME:()=>i,FETCH:()=>_,FETCH_BODY:()=>v,FETCH_DONE:()=>m,FETCH_START:()=>p,FN_END:()=>c,FN_START:()=>s,INTERACTION:()=>l,INTERACTION_API:()=>d,INTERACTION_EVENTS:()=>o,JSONP_END:()=>b,JSONP_NODE:()=>g,JS_TIME:()=>T,MAX_TIMER_BUDGET:()=>a,REMAINING:()=>f,SPA_NODE:()=>h,START:()=>w,originalSetTimeout:()=>y});var n=r(5763);const i=r(3325).D.spa,o=["click","submit","keypress","keydown","keyup","change"],a=999,s="fn-start",c="fn-end",u="cb-start",d="api-ixn-",f="remaining",l="interaction",h="spaNode",g="jsonpNode",p="fetch-start",m="fetch-done",v="fetch-body-",b="jsonp-end",y=n.Yu.ST,w="-start",x="-end",A="-body",E="cb"+x,T="jsTime",_="fetch"},5938:(e,t,r)=>{r.d(t,{W:()=>o});var n=r(5763),i=r(2177);class o{constructor(e,t,r){this.agentIdentifier=e,this.aggregator=t,this.ee=i.ee.get(e,(0,n.OP)(this.agentIdentifier).isolatedBacklog),this.featureName=r,this.blocked=!1}}},9144:(e,t,r)=>{r.d(t,{j:()=>m});var n=r(3325),i=r(5763),o=r(5546),a=r(2177),s=r(7894),c=r(8e3),u=r(3960),d=r(385),f=r(50),l=r(3081),h=r(8632);function g(){const e=(0,h.gG)();["setErrorHandler","finished","addToTrace","inlineHit","addRelease","addPageAction","setCurrentRouteName","setPageViewName","setCustomAttribute","interaction","noticeError","setUserId"].forEach((t=>{e[t]=function(){for(var r=arguments.length,n=new Array(r),i=0;i 1?r-1:0),i=1;i {e.exposed&&e.api[t]&&o.push(e.api[t](...n))})),o.length>1?o:o[0]}(t,...n)}}))}var p=r(2587);function m(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:{},m=arguments.length>2?arguments[2]:void 0,v=arguments.length>3?arguments[3]:void 0,{init:b,info:y,loader_config:w,runtime:x={loaderType:m},exposed:A=!0}=t;const E=(0,h.gG)();y||(b=E.init,y=E.info,w=E.loader_config),(0,i.Dg)(e,b||{}),(0,i.GE)(e,w||{}),(0,i.sU)(e,x),y.jsAttributes??={},d.v6&&(y.jsAttributes.isWorker=!0),(0,i.CX)(e,y),g();const T=function(e,t){t||(0,c.R)(e,"api");const h={};var g=a.ee.get(e),p=g.get("tracer"),m="api-",v=m+"ixn-";function b(t,r,n,o){const a=(0,i.C5)(e);return null===r?delete a.jsAttributes[t]:(0,i.CX)(e,{...a,jsAttributes:{...a.jsAttributes,[t]:r}}),x(m,n,!0,o||null===r?"session":void 0)(t,r)}function y(){}["setErrorHandler","finished","addToTrace","inlineHit","addRelease"].forEach((e=>h[e]=x(m,e,!0,"api"))),h.addPageAction=x(m,"addPageAction",!0,n.D.pageAction),h.setCurrentRouteName=x(m,"routeName",!0,n.D.spa),h.setPageViewName=function(t,r){if("string"==typeof t)return"/"!==t.charAt(0)&&(t="/"+t),(0,i.OP)(e).customTransaction=(r||"http://custom.transaction")+t,x(m,"setPageViewName",!0)()},h.setCustomAttribute=function(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2];if("string"==typeof e){if(["string","number"].includes(typeof t)||null===t)return b(e,t,"setCustomAttribute",r);(0,f.Z)("Failed to execute setCustomAttribute.\nNon-null value must be a string or number type, but a type of was provided."))}else(0,f.Z)("Failed to execute setCustomAttribute.\nName must be a string type, but a type of was provided."))},h.setUserId=function(e){if("string"==typeof e||null===e)return b("enduser.id",e,"setUserId",!0);(0,f.Z)("Failed to execute setUserId.\nNon-null value must be a string type, but a type of was provided."))},h.interaction=function(){return(new y).get()};var w=y.prototype={createTracer:function(e,t){var r={},i=this,a="function"==typeof t;return(0,o.p)(v+"tracer",[(0,s.z)(),e,r],i,n.D.spa,g),function(){if(p.emit((a?"":"no-")+"fn-start",[(0,s.z)(),i,a],r),a)try{return t.apply(this,arguments)}catch(e){throw p.emit("fn-err",[arguments,this,"string"==typeof e?new Error(e):e],r),e}finally{p.emit("fn-end",[(0,s.z)()],r)}}}};function x(e,t,r,i){return function(){return(0,o.p)(l.xS,["API/"+t+"/called"],void 0,n.D.metrics,g),i&&(0,o.p)(e+t,[(0,s.z)(),...arguments],r?null:this,i,g),r?void 0:this}}function A(){r.e(439).then(r.bind(r,7438)).then((t=>{let{setAPI:r}=t;r(e),(0,c.L)(e,"api")})).catch((()=>(0,f.Z)("Downloading runtime APIs failed...")))}return["actionText","setName","setAttribute","save","ignore","onEnd","getContext","end","get"].forEach((e=>{w[e]=x(v,e,void 0,n.D.spa)})),h.noticeError=function(e,t){"string"==typeof e&&(e=new Error(e)),(0,o.p)(l.xS,["API/noticeError/called"],void 0,n.D.metrics,g),(0,o.p)("err",[e,(0,s.z)(),!1,t],void 0,n.D.jserrors,g)},d.il?(0,u.b)((()=>A()),!0):A(),h}(e,v);return(0,h.Qy)(e,T,"api"),(0,h.Qy)(e,A,"exposed"),(0,h.EZ)("activatedFeatures",p.T),T}},3325:(e,t,r)=>{r.d(t,{D:()=>n,p:()=>i});const n={ajax:"ajax",jserrors:"jserrors",metrics:"metrics",pageAction:"page_action",pageViewEvent:"page_view_event",pageViewTiming:"page_view_timing",sessionReplay:"session_replay",sessionTrace:"session_trace",spa:"spa"},i={[n.pageViewEvent]:1,[n.pageViewTiming]:2,[n.metrics]:3,[n.jserrors]:4,[n.ajax]:5,[n.sessionTrace]:6,[n.pageAction]:7,[n.spa]:8,[n.sessionReplay]:9}}},n={};function i(e){var t=n[e];if(void 0!==t)return t.exports;var o=n[e]={exports:{}};return r[e](o,o.exports,i),o.exports}i.m=r,i.d=(e,t)=>{for(var r in t)i.o(t,r)&&!i.o(e,r)&&Object.defineProperty(e,r,{enumerable:!0,get:t[r]})},i.f={},i.e=e=>Promise.all(Object.keys(i.f).reduce(((t,r)=>(i.f[r](e,t),t)),[])),i.u=e=>(({78:"page_action-aggregate",147:"metrics-aggregate",242:"session-manager",317:"jserrors-aggregate",348:"page_view_timing-aggregate",412:"lazy-feature-loader",439:"async-api",538:"recorder",590:"session_replay-aggregate",675:"compressor",733:"session_trace-aggregate",786:"page_view_event-aggregate",873:"spa-aggregate",898:"ajax-aggregate"}[e]||e)+"."+{78:"ac76d497",147:"3dc53903",148:"1a20d5fe",242:"2a64278a",317:"49e41428",348:"bd6de33a",412:"2f55ce66",439:"30bd804e",538:"1b18459f",590:"cf0efb30",675:"ae9f91a8",733:"83105561",786:"06482edd",860:"03a8b7a5",873:"e6b09d52",898:"998ef92b"}[e]+"-1.236.0.min.js"),i.o=(e,t)=>Object.prototype.hasOwnProperty.call(e,t),e={},t="NRBA:",i.l=(r,n,o,a)=>{if(e[r])e[r].push(n);else{var s,c;if(void 0!==o)for(var u=document.getElementsByTagName("script"),d=0;d {s.onerror=s.onload=null,clearTimeout(h);var i=e[r];if(delete e[r],s.parentNode&&s.parentNode.removeChild(s),i&&i.forEach((e=>e(n))),t)return t(n)},h=setTimeout(l.bind(null,void 0,{type:"timeout",target:s}),12e4);s.onerror=l.bind(null,s.onerror),s.onload=l.bind(null,s.onload),c&&document.head.appendChild(s)}},i.r=e=>{"undefined"!=typeof Symbol&&Symbol.toStringTag&&Object.defineProperty(e,Symbol.toStringTag,{value:"Module"}),Object.defineProperty(e,"__esModule",{value:!0})},i.j=364,i.p="https://js-agent.newrelic.com/",(()=>{var e={364:0,953:0};i.f.j=(t,r)=>{var n=i.o(e,t)?e[t]:void 0;if(0!==n)if(n)r.push(n[2]);else{var o=new Promise(((r,i)=>n=e[t]=[r,i]));r.push(n[2]=o);var a=i.p+i.u(t),s=new Error;i.l(a,(r=>{if(i.o(e,t)&&(0!==(n=e[t])&&(e[t]=void 0),n)){var o=r&&("load"===r.type?"missing":r.type),a=r&&r.target&&r.target.src;s.message="Loading chunk "+t+" failed.\n("+o+": "+a+")",s.name="ChunkLoadError",s.type=o,s.request=a,n[1](s)}}),"chunk-"+t,t)}};var t=(t,r)=>{var n,o,[a,s,c]=r,u=0;if(a.some((t=>0!==e[t]))){for(n in s)i.o(s,n)&&(i.m[n]=s[n]);if(c)c(i)}for(t&&t(r);u {i.r(o);var e=i(3325),t=i(5763);const r=Object.values(e.D);function n(e){const n={};return r.forEach((r=>{n[r]=function(e,r){return!1!==(0,t.Mt)(r,"".concat(e,".enabled"))}(r,e)})),n}var a=i(9144);var s=i(5546),c=i(385),u=i(8e3),d=i(5938),f=i(3960),l=i(50);class h extends d.W{constructor(e,t,r){let n=!(arguments.length>3&&void 0!==arguments[3])||arguments[3];super(e,t,r),this.auto=n,this.abortHandler,this.featAggregate,this.onAggregateImported,n&&(0,u.R)(e,r)}importAggregator(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:{};if(this.featAggregate||!this.auto)return;const r=c.il&&!0===(0,t.Mt)(this.agentIdentifier,"privacy.cookies_enabled");let n;this.onAggregateImported=new Promise((e=>{n=e}));const o=async()=>{let t;try{if(r){const{setupAgentSession:e}=await Promise.all([i.e(860),i.e(242)]).then(i.bind(i,3228));t=e(this.agentIdentifier)}}catch(e){(0,l.Z)("A problem occurred when starting up session manager. This page will not start or extend any session.",e)}try{if(!this.shouldImportAgg(this.featureName,t))return void(0,u.L)(this.agentIdentifier,this.featureName);const{lazyFeatureLoader:r}=await i.e(412).then(i.bind(i,8582)),{Aggregate:o}=await r(this.featureName,"aggregate");this.featAggregate=new o(this.agentIdentifier,this.aggregator,e),n(!0)}catch(e){(0,l.Z)("Downloading and initializing ".concat(this.featureName," failed..."),e),this.abortHandler?.(),n(!1)}};c.il?(0,f.b)((()=>o()),!0):o()}shouldImportAgg(r,n){return r!==e.D.sessionReplay||!1!==(0,t.Mt)(this.agentIdentifier,"session_trace.enabled")&&(!!n?.isNew||!!n?.state.sessionReplay)}}var g=i(7633),p=i(7894);class m extends h{static featureName=g.t9;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];if(super(r,n,g.t9,i),("undefined"==typeof PerformanceNavigationTiming||c.Tt)&&"undefined"!=typeof PerformanceTiming){const n=(0,t.OP)(r);n[g.Dz]=Math.max(Date.now()-n.offset,0),(0,f.K)((()=>n[g.qw]=Math.max((0,p.z)()-n[g.Dz],0))),(0,f.b)((()=>{const t=(0,p.z)();n[g.OJ]=Math.max(t-n[g.Dz],0),(0,s.p)("timing",["load",t],void 0,e.D.pageViewTiming,this.ee)}))}this.importAggregator()}}var v=i(1117),b=i(1284);class y extends v.w{constructor(e){super(e),this.aggregatedData={}}store(e,t,r,n,i){var o=this.getBucket(e,t,r,i);return o.metrics=function(e,t){t||(t={count:0});return t.count+=1,(0,b.D)(e,(function(e,r){t[e]=w(r,t[e])})),t}(n,o.metrics),o}merge(e,t,r,n,i){var o=this.getBucket(e,t,n,i);if(o.metrics){var a=o.metrics;a.count+=r.count,(0,b.D)(r,(function(e,t){if("count"!==e){var n=a[e],i=r[e];i&&!i.c?a[e]=w(i.t,n):a[e]=function(e,t){if(!t)return e;t.c||(t=x(t.t));return t.min=Math.min(e.min,t.min),t.max=Math.max(e.max,t.max),t.t+=e.t,t.sos+=e.sos,t.c+=e.c,t}(i,a[e])}}))}else o.metrics=r}storeMetric(e,t,r,n){var i=this.getBucket(e,t,r);return i.stats=w(n,i.stats),i}getBucket(e,t,r,n){this.aggregatedData[e]||(this.aggregatedData[e]={});var i=this.aggregatedData[e][t];return i||(i=this.aggregatedData[e][t]={params:r||{}},n&&(i.custom=n)),i}get(e,t){return t?this.aggregatedData[e]&&this.aggregatedData[e][t]:this.aggregatedData[e]}take(e){for(var t={},r="",n=!1,i=0;i t.max&&(t.max=e),e 2&&void 0!==arguments[2])||arguments[2];super(e,r,j.t,n),c.il&&((0,t.OP)(e).initHidden=Boolean("hidden"===document.visibilityState),(0,N.N)((()=>(0,s.p)("docHidden",[(0,p.z)()],void 0,j.t,this.ee)),!0),(0,O.bP)("pagehide",(()=>(0,s.p)("winPagehide",[(0,p.z)()],void 0,j.t,this.ee))),this.importAggregator())}}var P=i(3081);class C extends h{static featureName=P.t9;constructor(e,t){let r=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,P.t9,r),this.importAggregator()}}var R,I=i(2210),k=i(1214),H=i(2177),L={};try{R=localStorage.getItem("__nr_flags").split(","),console&&"function"==typeof console.log&&(L.console=!0,-1!==R.indexOf("dev")&&(L.dev=!0),-1!==R.indexOf("nr_dev")&&(L.nrDev=!0))}catch(e){}function z(e){try{L.console&&z(e)}catch(e){}}L.nrDev&&H.ee.on("internal-error",(function(e){z(e.stack)})),L.dev&&H.ee.on("fn-err",(function(e,t,r){z(r.stack)})),L.dev&&(z("NR AGENT IN DEVELOPMENT MODE"),z("flags: "+(0,b.D)(L,(function(e,t){return e})).join(", ")));var M=i(6660);class B extends h{static featureName=M.t;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(r,n,M.t,i),this.skipNext=0;try{this.removeOnAbort=new AbortController}catch(e){}const o=this;o.ee.on("fn-start",(function(e,t,r){o.abortHandler&&(o.skipNext+=1)})),o.ee.on("fn-err",(function(t,r,n){o.abortHandler&&!n[M.A]&&((0,I.X)(n,M.A,(function(){return!0})),this.thrown=!0,(0,s.p)("err",[n,(0,p.z)()],void 0,e.D.jserrors,o.ee))})),o.ee.on("fn-end",(function(){o.abortHandler&&!this.thrown&&o.skipNext>0&&(o.skipNext-=1)})),o.ee.on("internal-error",(function(t){(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,o.ee)})),this.origOnerror=c._A.onerror,c._A.onerror=this.onerrorHandler.bind(this),c._A.addEventListener("unhandledrejection",(t=>{const r=function(e){let t="Unhandled Promise Rejection: ";if(e instanceof Error)try{return e.message=t+e.message,e}catch(t){return e}if(void 0===e)return new Error(t);try{return new Error(t+(0,D.P)(e))}catch(e){return new Error(t)}}(t.reason);(0,s.p)("err",[r,(0,p.z)(),!1,{unhandledPromiseRejection:1}],void 0,e.D.jserrors,this.ee)}),(0,O.m$)(!1,this.removeOnAbort?.signal)),(0,k.gy)(this.ee),(0,k.BV)(this.ee),(0,k.em)(this.ee),(0,t.OP)(r).xhrWrappable&&(0,k.Kf)(this.ee),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}onerrorHandler(t,r,n,i,o){"function"==typeof this.origOnerror&&this.origOnerror(...arguments);try{this.skipNext?this.skipNext-=1:(0,s.p)("err",[o||new F(t,r,n),(0,p.z)()],void 0,e.D.jserrors,this.ee)}catch(t){try{(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,this.ee)}catch(e){}}return!1}}function F(e,t,r){this.message=e||"Uncaught error with no additional information",this.sourceURL=t,this.line=r}let U=1;const q="nr@id";function G(e){const t=typeof e;return!e||"object"!==t&&"function"!==t?-1:e===c._A?0:(0,I.X)(e,q,(function(){return U++}))}function V(e){if("string"==typeof e&&e.length)return e.length;if("object"==typeof e){if("undefined"!=typeof ArrayBuffer&&e instanceof ArrayBuffer&&e.byteLength)return e.byteLength;if("undefined"!=typeof Blob&&e instanceof Blob&&e.size)return e.size;if(!("undefined"!=typeof FormData&&e instanceof FormData))try{return(0,D.P)(e).length}catch(e){return}}}var X=i(7243);class W{constructor(e){this.agentIdentifier=e,this.generateTracePayload=this.generateTracePayload.bind(this),this.shouldGenerateTrace=this.shouldGenerateTrace.bind(this)}generateTracePayload(e){if(!this.shouldGenerateTrace(e))return null;var r=(0,t.DL)(this.agentIdentifier);if(!r)return null;var n=(r.accountID||"").toString()||null,i=(r.agentID||"").toString()||null,o=(r.trustKey||"").toString()||null;if(!n||!i)return null;var a=(0,_.M)(),s=(0,_.Ht)(),c=Date.now(),u={spanId:a,traceId:s,timestamp:c};return(e.sameOrigin||this.isAllowedOrigin(e)&&this.useTraceContextHeadersForCors())&&(u.traceContextParentHeader=this.generateTraceContextParentHeader(a,s),u.traceContextStateHeader=this.generateTraceContextStateHeader(a,c,n,i,o)),(e.sameOrigin&&!this.excludeNewrelicHeader()||!e.sameOrigin&&this.isAllowedOrigin(e)&&this.useNewrelicHeaderForCors())&&(u.newrelicHeader=this.generateTraceHeader(a,s,c,n,i,o)),u}generateTraceContextParentHeader(e,t){return"00-"+t+"-"+e+"-01"}generateTraceContextStateHeader(e,t,r,n,i){return i+"@nr=0-1-"+r+"-"+n+"-"+e+"----"+t}generateTraceHeader(e,t,r,n,i,o){if(!("function"==typeof c._A?.btoa))return null;var a={v:[0,1],d:{ty:"Browser",ac:n,ap:i,id:e,tr:t,ti:r}};return o&&n!==o&&(a.d.tk=o),btoa((0,D.P)(a))}shouldGenerateTrace(e){return this.isDtEnabled()&&this.isAllowedOrigin(e)}isAllowedOrigin(e){var r=!1,n={};if((0,t.Mt)(this.agentIdentifier,"distributed_tracing")&&(n=(0,t.P_)(this.agentIdentifier).distributed_tracing),e.sameOrigin)r=!0;else if(n.allowed_origins instanceof Array)for(var i=0;i 2&&void 0!==arguments[2])||arguments[2];super(r,n,Z.t,i),(0,t.OP)(r).xhrWrappable&&(this.dt=new W(r),this.handler=(e,t,r,n)=>(0,s.p)(e,t,r,n,this.ee),(0,k.u5)(this.ee),(0,k.Kf)(this.ee),function(r,n,i,o){function a(e){var t=this;t.totalCbs=0,t.called=0,t.cbTime=0,t.end=E,t.ended=!1,t.xhrGuids={},t.lastSize=null,t.loadCaptureCalled=!1,t.params=this.params||{},t.metrics=this.metrics||{},e.addEventListener("load",(function(r){_(t,e)}),(0,O.m$)(!1)),c.IF||e.addEventListener("progress",(function(e){t.lastSize=e.loaded}),(0,O.m$)(!1))}function s(e){this.params={method:e[0]},T(this,e[1]),this.metrics={}}function u(e,n){var i=(0,t.DL)(r);i.xpid&&this.sameOrigin&&n.setRequestHeader("X-NewRelic-ID",i.xpid);var a=o.generateTracePayload(this.parsedOrigin);if(a){var s=!1;a.newrelicHeader&&(n.setRequestHeader("newrelic",a.newrelicHeader),s=!0),a.traceContextParentHeader&&(n.setRequestHeader("traceparent",a.traceContextParentHeader),a.traceContextStateHeader&&n.setRequestHeader("tracestate",a.traceContextStateHeader),s=!0),s&&(this.dt=a)}}function d(e,t){var r=this.metrics,i=e[0],o=this;if(r&&i){var a=V(i);a&&(r.txSize=a)}this.startTime=(0,p.z)(),this.listener=function(e){try{"abort"!==e.type||o.loadCaptureCalled||(o.params.aborted=!0),("load"!==e.type||o.called===o.totalCbs&&(o.onloadCalled||"function"!=typeof t.onload)&&"function"==typeof o.end)&&o.end(t)}catch(e){try{n.emit("internal-error",[e])}catch(e){}}};for(var s=0;s 1?e[1]=i:e.push(i)}else e[0]&&e[0].headers&&s(e[0].headers,n)&&(this.dt=n);function s(e,t){var r=!1;return t.newrelicHeader&&(e.set("newrelic",t.newrelicHeader),r=!0),t.traceContextParentHeader&&(e.set("traceparent",t.traceContextParentHeader),t.traceContextStateHeader&&e.set("tracestate",t.traceContextStateHeader),r=!0),r}}function x(e,t){this.params={},this.metrics={},this.startTime=(0,p.z)(),this.dt=t,e.length>=1&&(this.target=e[0]),e.length>=2&&(this.opts=e[1]);var r,n=this.opts||{},i=this.target;"string"==typeof i?r=i:"object"==typeof i&&i instanceof Y?r=i.url:c._A?.URL&&"object"==typeof i&&i instanceof URL&&(r=i.href),T(this,r);var o=(""+(i&&i instanceof Y&&i.method||n.method||"GET")).toUpperCase();this.params.method=o,this.txSize=V(n.body)||0}function A(t,r){var n;this.endTime=(0,p.z)(),this.params||(this.params={}),this.params.status=r?r.status:0,"string"==typeof this.rxSize&&this.rxSize.length>0&&(n=+this.rxSize);var o={txSize:this.txSize,rxSize:n,duration:(0,p.z)()-this.startTime};i("xhr",[this.params,o,this.startTime,this.endTime,"fetch"],this,e.D.ajax)}function E(t){var r=this.params,n=this.metrics;if(!this.ended){this.ended=!0;for(var o=0;o 2&&void 0!==arguments[2])||arguments[2];super(e,t,we.t,r),this.importAggregator()}}new class{constructor(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:(0,_.ky)(16);c._A?(this.agentIdentifier=t,this.sharedAggregator=new y({agentIdentifier:this.agentIdentifier}),this.features={},this.desiredFeatures=new Set(e.features||[]),this.desiredFeatures.add(m),Object.assign(this,(0,a.j)(this.agentIdentifier,e,e.loaderType||"agent")),this.start()):(0,l.Z)("Failed to initial the agent. Could not determine the runtime environment.")}get config(){return{info:(0,t.C5)(this.agentIdentifier),init:(0,t.P_)(this.agentIdentifier),loader_config:(0,t.DL)(this.agentIdentifier),runtime:(0,t.OP)(this.agentIdentifier)}}start(){const t="features";try{const r=n(this.agentIdentifier),i=[...this.desiredFeatures];i.sort(((t,r)=>e.p[t.featureName]-e.p[r.featureName])),i.forEach((t=>{if(r[t.featureName]||t.featureName===e.D.pageViewEvent){const n=function(t){switch(t){case e.D.ajax:return[e.D.jserrors];case e.D.sessionTrace:return[e.D.ajax,e.D.pageViewEvent];case e.D.sessionReplay:return[e.D.sessionTrace];case e.D.pageViewTiming:return[e.D.pageViewEvent];default:return[]}}(t.featureName);n.every((e=>r[e]))||(0,l.Z)("".concat(t.featureName," is enabled but one or more dependent features has been disabled (").concat((0,D.P)(n),"). This may cause unintended consequences or missing data...")),this.features[t.featureName]=new t(this.agentIdentifier,this.sharedAggregator)}})),(0,T.Qy)(this.agentIdentifier,this.features,t)}catch(e){(0,l.Z)("Failed to initialize all enabled instrument classes (agent aborted) -",e);for(const e in this.features)this.features[e].abortHandler?.();const r=(0,T.fP)();return delete r.initializedAgents[this.agentIdentifier]?.api,delete r.initializedAgents[this.agentIdentifier]?.[t],delete this.sharedAggregator,r.ee?.abort(),delete r.ee?.get(this.agentIdentifier),!1}}}({features:[J,m,S,class extends h{static featureName=oe;constructor(t,r){if(super(t,r,oe,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;const n=this.ee;let i;(0,k.QU)(n),this.eventsEE=(0,k.em)(n),this.eventsEE.on(se,(function(e,t){this.bstStart=(0,p.z)()})),this.eventsEE.on(ae,(function(t,r){(0,s.p)("bst",[t[0],r,this.bstStart,(0,p.z)()],void 0,e.D.sessionTrace,n)})),n.on(ce+ne,(function(e){this.time=(0,p.z)(),this.startPath=location.pathname+location.hash})),n.on(ce+ie,(function(t){(0,s.p)("bstHist",[location.pathname+location.hash,this.startPath,this.time],void 0,e.D.sessionTrace,n)}));try{i=new PerformanceObserver((t=>{const r=t.getEntries();(0,s.p)(te,[r],void 0,e.D.sessionTrace,n)})),i.observe({type:re,buffered:!0})}catch(e){}this.importAggregator({resourceObserver:i})}},C,xe,B,class extends h{static featureName=de;constructor(e,r){if(super(e,r,de,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;if(!(0,t.OP)(e).xhrWrappable)return;try{this.removeOnAbort=new AbortController}catch(e){}let n,i=0;const o=this.ee.get("tracer"),a=(0,k._L)(this.ee),s=(0,k.Lg)(this.ee),u=(0,k.BV)(this.ee),d=(0,k.Kf)(this.ee),f=this.ee.get("events"),l=(0,k.u5)(this.ee),h=(0,k.QU)(this.ee),g=(0,k.Gm)(this.ee);function m(e,t){h.emit("newURL",[""+window.location,t])}function v(){i++,n=window.location.hash,this[ve]=(0,p.z)()}function b(){i--,window.location.hash!==n&&m(0,!0);var e=(0,p.z)();this[pe]=~~this[pe]+e-this[ve],this[ye]=e}function y(e,t){e.on(t,(function(){this[t]=(0,p.z)()}))}this.ee.on(ve,v),s.on(be,v),a.on(be,v),this.ee.on(ye,b),s.on(ge,b),a.on(ge,b),this.ee.buffer([ve,ye,"xhr-resolved"],this.featureName),f.buffer([ve],this.featureName),u.buffer(["setTimeout"+le,"clearTimeout"+fe,ve],this.featureName),d.buffer([ve,"new-xhr","send-xhr"+fe],this.featureName),l.buffer([me+fe,me+"-done",me+he+fe,me+he+le],this.featureName),h.buffer(["newURL"],this.featureName),g.buffer([ve],this.featureName),s.buffer(["propagate",be,ge,"executor-err","resolve"+fe],this.featureName),o.buffer([ve,"no-"+ve],this.featureName),a.buffer(["new-jsonp","cb-start","jsonp-error","jsonp-end"],this.featureName),y(l,me+fe),y(l,me+"-done"),y(a,"new-jsonp"),y(a,"jsonp-end"),y(a,"cb-start"),h.on("pushState-end",m),h.on("replaceState-end",m),window.addEventListener("hashchange",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("load",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("popstate",(function(){m(0,i>1)}),(0,O.m$)(!0,this.removeOnAbort?.signal)),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}],loaderType:"spa"})})(),window.NRBA=o})(); window.jQuery || document.write(' ') CKEDITOR_BASEPATH='https://f1000research.com/js/vendor/ckeditor/' window.reactTheme = 'research'; window.MathJax = { CommonHTML: { linebreaks: { automatic: true } }, 'HTML-CSS': { linebreaks: { automatic: true } }, SVG: { linebreaks: { automatic: true } }, AuthorInit: function() { MathJax.Hub.Register.MessageHook('End Process', function () { let timeout = false; // holder for timeout id const delay = 250; // delay after event is "complete" to run callback const reflowMath = function() { const dispFormulas = document.querySelectorAll('.disp-formula.panel'); if (!dispFormulas) { return; } for (const dispFormula of dispFormulas) { const child = dispFormula.querySelector('.MathJax_Preview').nextSibling.firstChild; const isMultiline = MathJax.Hub.getAllJax(dispFormula)[0].root.isMultiline; if (dispFormula.offsetWidth < child.offsetWidth || isMultiline) { MathJax.Hub.Queue(['Rerender', MathJax.Hub, dispFormula]); } } }; window.addEventListener('resize', function() { clearTimeout(timeout); // clear the timeout timeout = setTimeout(reflowMath, delay); // start timing for event "completion" }); }); }, }; if (window.location.hash == '#_=_'){ window.location = window.location.href.split('#')[0] } !function(f,b,e,v,n,t,s){if(f.fbq)return;n=f.fbq=function() {n.callMethod? n.callMethod.apply(n,arguments):n.queue.push(arguments)} ;if(!f._fbq)f._fbq=n; n.push=n;n.loaded=!0;n.version='2.0';n.queue=[];t=b.createElement(e);t.async=!0; t.src=v;s=b.getElementsByTagName(e)[0];s.parentNode.insertBefore(t,s)}(window, document,'script','https://connect.facebook.net/en_US/fbevents.js'); fbq('init', '1641728616063202'); fbq('track', "PixelInitialized", {}); (function(h,o,t,j,a,r){ h.hj=h.hj||function(){(h.hj.q=h.hj.q||[]).push(arguments)}; h._hjSettings={hjid:2318163,hjsv:6}; a=o.getElementsByTagName('head')[0]; r=o.createElement('script');r.async=1; r.src=t+h._hjSettings.hjid+j+h._hjSettings.hjsv; a.appendChild(r); })(window,document,'https://static.hotjar.com/c/hotjar-','.js?sv='); search file_upload Submit your research search menu close search Browse Gateways & Collections How to Publish Submit your Research My Submissions Article Guidelines Article Guidelines (New Versions) Open Data, Software and Code Guidelines Open Data and Accessible Source Materials Guidelines (HSS) Open Data, Software and Code Guidelines (PSE) Prepublication Checks Production Process Posters and Slides Guidelines Document Guidelines Article Processing Charges Peer Review Finding Article Reviewers About How it Works For Reviewers Our Advisors Policies Glossary FAQs For Developers Newsroom Contact My Research Submissions Content and Tracking Alerts My Details Sign In file_upload Submit your research { "@context": "https://schema.org", "@type": "ScholarlyArticle", "mainEntityOfPage": { "@type": "WebPage", "@id": "https://f1000research.com/articles/8-1044" }, "headline": "Force transduction by cadherin adhesions in morphogenesis", "datePublished": "2019-07-10T15:29:20", "dateModified": "2019-07-10T15:29:20", "author": [ { "@type": "Person", "name": "Willem-Jan Pannekoek" }, { "@type": "Person", "name": "Johan de Rooij" }, { "@type": "Person", "name": "Martijn Gloerich" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": "Mechanical forces drive the remodeling of tissues during morphogenesis. This relies on the transmission of forces between cells by cadherin-based adherens junctions, which couple the force-generating actomyosin cytoskeletons of neighboring cells. Moreover, components of cadherin adhesions adopt force-dependent conformations that induce changes in the composition of adherens junctions, enabling transduction of mechanical forces into an intracellular response. Cadherin mechanotransduction can mediate reinforcement of cell–cell adhesions to withstand forces but also induce biochemical signaling to regulate cell behavior or direct remodeling of cell–cell adhesions to enable cell rearrangements. By transmission and transduction of mechanical forces, cadherin adhesions coordinate cellular behaviors underlying morphogenetic processes of collective cell migration, cell division, and cell intercalation. Here, we review recent advances in our understanding of this central role of cadherin adhesions in force-dependent regulation of morphogenesis." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/8-1044", "name": "Force transduction by cadherin adhesions in morphogenesis" } } ] } Home Browse Force transduction by cadherin adhesions in morphogenesis ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Pannekoek WJ, de Rooij J and Gloerich M. Force transduction by cadherin adhesions in morphogenesis [version 1; peer review: 3 approved] . F1000Research 2019, 8 (F1000 Faculty Rev):1044 ( https://doi.org/10.12688/f1000research.18779.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Review Force transduction by cadherin adhesions in morphogenesis [version 1; peer review: 3 approved] Willem-Jan Pannekoek 1 , Johan de Rooij 1 , Martijn Gloerich https://orcid.org/0000-0002-0034-4642 1 Willem-Jan Pannekoek 1 , Johan de Rooij 1 , Martijn Gloerich https://orcid.org/0000-0002-0034-4642 1 PUBLISHED 10 Jul 2019 Author details Author details 1 Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands Willem-Jan Pannekoek Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing Johan de Rooij Roles: Writing – Review & Editing Martijn Gloerich Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Mechanical forces drive the remodeling of tissues during morphogenesis. This relies on the transmission of forces between cells by cadherin-based adherens junctions, which couple the force-generating actomyosin cytoskeletons of neighboring cells. Moreover, components of cadherin adhesions adopt force-dependent conformations that induce changes in the composition of adherens junctions, enabling transduction of mechanical forces into an intracellular response. Cadherin mechanotransduction can mediate reinforcement of cell–cell adhesions to withstand forces but also induce biochemical signaling to regulate cell behavior or direct remodeling of cell–cell adhesions to enable cell rearrangements. By transmission and transduction of mechanical forces, cadherin adhesions coordinate cellular behaviors underlying morphogenetic processes of collective cell migration, cell division, and cell intercalation. Here, we review recent advances in our understanding of this central role of cadherin adhesions in force-dependent regulation of morphogenesis. READ ALL READ LESS Keywords E-cadherin, adherens junction, mechanical force, mechanotransduction, collective migration, spindle orientation, intercalation Corresponding Author(s) Martijn Gloerich ( [email protected] ) Close Corresponding author: Martijn Gloerich Competing interests: No competing interests were disclosed. Grant information: JdR is supported by the European Commission (H2020-FETPROACT-01-2016-731957), and MG is supported by the Netherlands Organisation for Scientific Research (NWO; 016.Vidi.189.166 and NWO gravitational program CancerGenomiCs.nl). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2019 Pannekoek WJ et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Pannekoek WJ, de Rooij J and Gloerich M. Force transduction by cadherin adhesions in morphogenesis [version 1; peer review: 3 approved] . F1000Research 2019, 8 (F1000 Faculty Rev):1044 ( https://doi.org/10.12688/f1000research.18779.1 ) First published: 10 Jul 2019, 8 (F1000 Faculty Rev):1044 ( https://doi.org/10.12688/f1000research.18779.1 ) Latest published: 10 Jul 2019, 8 (F1000 Faculty Rev):1044 ( https://doi.org/10.12688/f1000research.18779.1 ) Introduction Morphogenesis comprises the collection of processes that shape tissues and organisms, which relies on the coordinated regulation of cell behavior. Though most apparent throughout embryonic development, morphogenetic processes continue to play a role in adult tissues (for instance, during tissue regeneration upon wounding as well as pathological conditions such as cancer invasion). Morphogenesis inherently is a mechanical process, as the coordinated generation of forces by cells is required to establish tissue shape 1 , 2 . In addition, forces exerted on cells by each other and their surroundings serve as instructive signals to which cells adapt their behavior. This depends on the ability of cells to sense and convert mechanical forces into a biochemical intracellular response (termed mechanotransduction), which is mediated by force-induced changes in the conformation of proteins and the composition of molecular complexes 3 , 4 . Mechanical forces typically originate from contraction of the actomyosin cytoskeleton, which is anchored to sites of adhesion and can thereby be transmitted to neighboring cells and the extracellular environment. As such, focal adhesions (at the cell–matrix interface) and adherens junctions (AJs) (at the cell–cell interface) represent key force transmission and transduction complexes of the cell. In recent years, many additional components of the cell cortex, including growth factor receptors, ion channels, caveolae, and the glycocalyx, have been identified to be responsive to forces 5 . In this review, we will focus on AJs, as they have emerged as central mechano-responsive components in the regulation of morphogenesis by intercellular forces. Mechanotransduction by adherens junctions The AJ is composed of transmembrane cadherin proteins (E-cadherin being the predominant cadherin in most epithelial tissues) that form homotypic dimers between neighboring cells . The cytosolic tail of cadherins compiles a large protein complex, which dynamically connects to the actomyosin cytoskeleton 6 . The core cadherin complex consists of p120-catenin, which controls cadherin membrane localization, and β-catenin and α-catenin, which provide a link with filamentous actin ( Figure 1a ). Importantly, β-catenin–bound α-catenin forms a catch-bond interaction with F-actin that is strengthened when the complex experiences tensile force ( Figure 1a ) 7 , which is explained by the force-dependent exposure of a cryptic actin-binding site within α-catenin 8 . In addition to enhanced actin binding of α-catenin, other force-induced changes occur in the cadherin complex that regulate the organization of junctional actin, thereby reinforcing cadherin junctions. Most well studied is the exposure of a binding site within α-catenin for Vinculin ( Figure 1a ), which provides additional linkage of the cadherin complex with actin 9 – 12 and recruits several actin-modulating proteins 13 , 14 . Intriguingly, Vinculin was recently shown to form a force-stabilized linkage to F-actin that is directionally asymmetric 15 , suggesting that Vinculin may further contribute to junctional actin remodeling by organizing the polarity of actin filaments. In addition to Vinculin, numerous other actin assembly and remodeling proteins are recruited when the cadherin complex is under tension upon application of forces from neighboring cells or the actin cytoskeleton ( Figure 1b ). These bind either directly to α-catenin (Afadin 16 ) or indirectly through other junctional components or the actin cytoskeleton (RhoGEF114 17 , VASP 18 , TES 18 , and Zyxin 18 ). This large number of identified actin-associated proteins recruited to tensed cadherin junctions confers several layers of mechanical control of the AJ–actin link, potentially explaining the mild phenotype of selectively losing Vinculin in various tissues 19 – 21 . Figure 1. Mechanotransduction by the cadherin complex. ( a ) Tensile forces on the cadherin complex, exerted either by neighboring cells through its extracellular domain or by myosin-generation contraction of the actin cytoskeleton associated with its cytosolic tail, cause unfolding of α-catenin, enabling its interaction with Vinculin. The interaction between α-catenin and F-actin is regulated by force as well, as β-catenin–bound α-catenin forms a catch-bond interaction with F-actin that shifts from a weakly bound to strongly bound state with increasing tension. Mechanical force can also influence transdimer interactions formed by the extracellular domain of E-cadherin, as X-dimer configurations of the transdimer form a catch-bond interaction whose lifetime increases with force (not shown) 37 . ( b ) Numerous proteins that are recruited to cadherin adhesions in a tension-dependent manner have been identified and show either increased (blue) or decreased (red) association with the cadherin complex upon increased tensile force. Dashed lines indicate tension-dependent adherens junction (AJ) components of which the molecular mechanism underlying association with the cadherin complex has not yet been resolved. α-cat, α-catenin; β-cat, β-catenin; p120, p120-catenin. By mechanically coupling the actomyosin network of neighboring cells, cadherin adhesions are essential for the transmission of forces between individual cells. As a result, cell within tissues develop collective contractility that allows them to coordinate morphogenetic cell rearrangements in tissues 2 , 22 , 23 . Moreover, the different mechanisms to transduce force into regulation of the organization of the actin cytoskeleton and its association with the cadherin complex strengthen cell–cell adhesions, enabling them to maintain integrity of tissues upon fluctuations in intercellular stresses. However, the cellular responses to junctional force reach much further, impacting, for instance, the cell cycle and cell division 24 , 25 , cell migration 26 , 27 , and cell metabolism 28 . This is mediated by force-regulated association of the cadherin complex with transcriptional activators (for example, β-catenin and YAP 24 , 29 ), kinases (for example, LKB1/AMPK 28 ), and interactors of microtubules and intermediate filaments ( Figure 1b ) 25 , 26 . E-cadherin thus should be envisioned not as a static mediator of cell–cell adhesion but rather as a dynamic sensor of tensile forces that instructs cellular behavior. In this way, E-cadherin fulfills a central role in transducing cellular forces to coordinate morphogenesis, as it instructs several processes that direct tissue shape, including collective migration, tissue growth, and cell–cell intercalation. Below, we will discuss recent advances in our understanding of the role of E-cadherin in the force-dependent regulation of these morphogenetic processes. Cadherin mechanotransduction in collective migration Tissue rearrangement during morphogenesis can be achieved by collective migration of groups or sheets of cells, which move while retaining adhesion between individual cells. These adhesions enable cell-to-cell communication to coordinate the direction of motion. As a result, cell clusters migrate more efficiently and persistently than isolated cells 30 . Moreover, migrating as a collective enables epithelial clusters to follow specific guidance cues while single cells or monolayers lacking AJs fail to do so 27 , 31 – 33 . It has been well established that cadherin-based adhesions enable collective migration by coupling cells to one another and by transmitting forces between cells to convey directional information (reviewed in 30 , 34 , 35 ). In migrating sheets, cells at the edge generate lamellipodia that protrude into the surrounding environment. These lamellipodia adhere to the surface and generate traction forces required for forward pulling of the cells 30 , 35 . Importantly, the pulling forces are exerted not only by these cells but by all cells in the cell sheet, which is coordinated via intercellular force transmission 36 . Cadherin junctions are the main force transducer between cells responsible for this, as the correlation between the orientations of migration and intercellular forces is lost by blocking E-cadherin function or depleting individual AJ components 38 , 39 . The migration direction of individual cells in a monolayer follows the local axis of maximum intercellular stresses 40 . More recently, it was shown that tension on AJs is anisotropic and highest at cell–cell contacts perpendicular to the migration direction 16 . This implies that forces acting locally at cell–cell contacts may help to establish the direction of motion. Indeed, experiments with α-catenin mutants in which Vinculin binding is perturbed, showed that transduction of forces by AJs is essential for coordinated motion in epithelial monolayers 16 , 41 . These results are corroborated in vivo , as shown by the convergence-extension defects observed in zebrafish expressing Vinculin binding–deficient α-catenin 42 . To establish directionality of collective migration, AJs not only transmit forces between cells but also transduce these forces into a cellular response to guide migration. Essentially, cell migration relies on the acquisition of a polarized cell state with Rac-induced (cryptic) lamellipodia protruding forward and Rho-mediated adhesion disassembly at the rear 43 . Accumulating evidence shows that force transduction at cell–cell junctions enables cells to coordinate this polarization and concomitant migration direction to their followers ( Figure 2a ) 16 , 27 , 44 . This is mediated, at least in part, by the force-induced release of Merlin from cell contacts, which induces polarized Rac activity and formation of cryptic lamellipodia in migrating epithelial layers 44 . While force-induced release of Merlin from tight junctions is implicated in this 44 , the association of Merlin with the cadherin complex was recently shown to be inhibited by tensile forces as well 45 . In migrating border cells in the Drosophila egg chamber, E-cadherin also transduces mechanical forces into Rac activation, resulting in protrusive activity at cell–cell contacts that are under elevated tension 27 . Ectopic expression of P-cadherin in migrating myoblasts further revealed that the Cdc42-GEF β-PIX is recruited to AJs in motile cells, presumably as a result of increased junctional tension 46 . This establishes the activation of Cdc42 and downstream Rac, thereby coordinating cell polarity 46 . The selective function of P-cadherin, and not other cadherins, in β-PIX regulation highlights that different cadherin proteins may have distinct functions in transducing mechanical forces to establish collective cell migration. In line with this, E- and P-cadherin were shown to have distinct contributions to the development of intercellular stresses in migrating epithelia 39 . Figure 2. Mechanotransduction at cell – cell junctions during collective cell migration. ( a ) Mechanotransduction at cell–cell junctions enables cells to coordinate cell polarization with their followers via several mechanisms that impinge on local activation of Rac, which establishes the formation of (cryptic) lamellipodia: (1) Tension on cell–cell junctions causes loss of Merlin from tight junctions (TJ), relieving its inhibition of Rac activation; (2) β-PIX is recruited by P-cadherin to adherens junctions (AJs) in migrating cells, presumably in a force-dependent manner, which results in activation of Cdc42 and downstream Rac1 to promote cell polarization; (3) Rho-mediated contractility at the rear of migrating cells induces the formation of cadherin fingers that extend into the trailing cells, which direct the formation of cryptic lamellipodia, presumably by contributing to the control of Rac activity. ( b ) During collective migration, force-dependent conformational opening of α-catenin occurs in an anisotropic manner and is highest at cell–cell junctions perpendicular to the migratory axis. This involves a feedback mechanism through α-catenin–mediated activation of Rho and its effector mDia that induces AJ remodeling and junction strengthening. Anisotropy in the force-dependent remodeling of AJs coordinates the direction of migration between cells, possibly by establishing preferential transmission of forces between cells in the direction of migration (red arrows). In addition to coordinating front–rear polarity, activation of Rho-family GTPases provides a positive feedback mechanism by reinforcing tension on E-cadherin junctions 16 , 27 . Conformational opening of α-catenin induces local activation of Rho and downstream mDia-mediated actin remodeling, which strengthens anisotropy in junctional tension in migrating epithelia ( Figure 2b ) 16 . Polarized Rho activity can also couple directional information between cells through the formation of specialized adhesion structures called cadherin fingers ( Figure 2a ). At the rear of migrating endothelial cells, local RhoA-induced contractility triggers the formation of cadherin fingers, which become engulfed in follower cells and direct the formation of cryptic lamellipodia. The highly curved membrane in the cadherin finger is potentially instructive for Rac activation in follower cells 47 , as many small GTPase regulators contain membrane curvature-recognizing domains 48 . As such, an important signaling cue can be induced by tension-mediated membrane curvature at the cell–cell junction interface 49 . Although the mechanisms of force transmission and transduction by AJs discussed above apply, in principle, to all cells in a migrating group, additional mechanisms may be at play at the migratory front. Migration is typically directed by a specified leader cell that is morphologically and functionally distinct from the rest of the cell population and that initiates and organizes the migration of follower cells 50 . Importantly, polarization and directed migration of the leader cell are regulated by transduction of forces at the cell–cell contact with its followers (reviewed in 30 , 51 ). Moreover, it was recently shown that tensile forces exerted by follower cells on prospective leaders induce their leader cell phenotype 52 . Another active function of the followers during collective migration was recently revealed for the very rear cells of the migrating cluster of neural crest cells 53 . Reminiscent of the purse-string mechanism of wound closure, these cells contract a supracellular actin cable that causes the cell cluster to be propelled forward 53 . Since both of these recently identified functions of follower and rear cells critically depend on force coordination between cells, it will be interesting to establish whether and how cadherin junctions contribute to this. Mechanical control of tissue growth The development of tissues into their correct size and proportions requires tight control of tissue growth and thus the rate and pattern of cell proliferation. Both of these are tightly regulated by, among other signals, mechanical forces that cells exert on each other. Seminal experiments in cultured monolayers revealed that patterns of local proliferation strongly correlate with the level of cellular traction forces 54 . This was shown to be dependent on force transmission by cadherin-based adhesions 54 , and specific analyses of intercellular forces demonstrated that the tendency of cells to proliferate correlates with the level of junctional tension 55 , 56 . Importantly, as tissues increase in cell density, junctional tension becomes reduced 57 because of a decrease in cell motility and cortical actomyosin contractility 57 , 58 . As such, sensing of intercellular tension provides a mechanism for cells to regulate density-dependent proliferation. At high cell density, proliferation ceases and this can be relieved by application of external stretch, as shown in both cultured cells 24 , 59 – 61 and the Drosophila wing disc 62 . In these experiments, mechanical stretch was shown to control proliferation by inducing cell cycle entry of quiescent cells 24 , 59 , 61 as well as promoting progression through the subsequent cell cycle phases 24 , 60 , 63 . Thus far, the contribution of tension-regulated proliferation to morphogenesis has been studied mainly in the developing Drosophila wing disc, in which transduction of junctional tension is directly linked to regulation of organ size 57 , 64 . Moreover, mechano-sensitive control of proliferation in the wing disc explains how developing tissues can maintain homogenous patterns of proliferation despite the presence of gradients of growth factors. In the center of the wing disc, high levels of growth factor–induced proliferation and concomitant increase in cell density decrease junctional tension 57 , 65 . This feeds back to reduce proliferation in this region and thereby balances local proliferation rates throughout the tissue to maintain tissue organization 66 . More recently, transduction of mechanical forces was also shown to regulate tissue size after development and, for instance, may adapt the size and composition of the Drosophila midgut to the feeding state of the animal 67 , 68 . Although additional mechano-sensing complexes may be involved, E-cadherin adhesions play a key role in transducing intercellular forces to the cell cycle. It has long been established that the presence of E-cadherin adhesions can inhibit proliferation by triggering cell cycle exit, a process termed contact inhibition of proliferation 69 . This involves inhibition of growth signals by E-cadherin adhesions, most notably through regulation of the Hippo signaling pathway 70 . The Hippo pathway consists of a cascade of kinases that ultimately establishes the nuclear exclusion of the transcriptional activator YAP (and its homologue TAZ) through phosphorylation by LATS kinases 71 . As recently demonstrated in the Drosophila wing disc and cultured epithelia, increased tension on E-cadherin junctions (for instance, by decreasing cell density or externally applied mechanical stretch) relieves this negative regulation, thereby promoting nuclear localization of YAP and cell cycle entry 24 , 57 , 72 , 73 . This is explained by force-induced opening of α-catenin that enables its interaction with proteins of the Ajuba/Zyxin family, which sequester LATS in an inactive state at AJs ( Figure 3 ) 57 , 64 , 72 , 73 . Several additional mechanisms may further contribute to the regulation of YAP upon fluctuations in tension on cadherin junctions 71 . These may in part regulate YAP independently of the Hippo pathway and impinge on sequestration of YAP itself at cadherin junctions 74 , 75 , modulate nuclear import by influencing nuclear pore dynamics 34 , attenuate nuclear export 45 , 76 , or influence YAP through modulation of the cortical cytoskeleton 59 , 78 . In addition to YAP signaling, force transduction by E-cadherin junctions can influence tissue growth through regulation of other proliferation pathways such as EGFR-mediated signaling 79 , 80 and β-catenin/TCF-mediated transcription. The molecular mechanism of the latter is best understood as mechanical tension on the cadherin complex induces phosphorylation of β-catenin on Y654 29 , 81 . This site may become increasingly exposed upon elevated junctional tension, and phosphorylation results in junctional dissociation of β-catenin to promote its translocation to the nucleus and TCF-mediated transcription 82 . Force-induced TCF activation has been linked to G 1 /S progression in mechanically stretched epithelial cultures 24 . Moreover, activation of this mechanical pathway in the mammalian intestine by ectopic application of forces to intestinal crypts was shown to trigger increased proliferation and concomitant hyperplasia 29 . Importantly, mechano-sensitive β-catenin/TCF signaling downstream of E-cadherin functions beyond the regulation of cell proliferation, and fulfills an evolutionary conserved role in cellular differentiation that underlies tissue specification during embryonic development 82 – 85 . E-cadherin mechanotransduction was recently also linked to the control of cell metabolism through LKB1-dependent junctional recruitment and activation of AMPK and concomitant ATP production 28 . Given the importance of metabolic regulation for the support of cell proliferation 86 , this could provide additional mechanisms by which force transduction by AJs impacts tissue growth. Figure 3. Regulation of YAP and β-catenin mediated transcription by junctional tension. Phosphorylation by LATS establishes the nuclear exclusion of the transcriptional activator YAP under conditions of low junctional tension. The conformational opening of α-catenin upon elevated tension on E-cadherin adhesions (for instance, at decreased cell density) enables junctional recruitment of Ajuba-family proteins. Ajuba sequesters LATS at cell–cell contacts and keeps it inactive at this site, allowing nuclear entry of YAP. Also, the related Zyxin-family protein TRIP6 localizes to AJs, through an interaction with Vinculin, and binds and inhibits LATS (not shown). Note that additional LATS-independent mechanisms have been proposed for the intercellular tension-dependent regulation of YAP (see text). The nuclear localization of the transcriptional coactivator β-catenin is also regulated by the level of tension on cadherin adhesions. Upon increased junctional tension, a subset of the junctional β-catenin pool is phosphorylated (on Y654 in mammals), resulting in its dissociation from E-cadherin. This promotes translocation of β-catenin into the nucleus to drive TCF-dependent gene transcription. Note that loss of tension on E-cadherin has also been shown to promote junctional release and transcriptional activity of β-catenin, independent of phosphorylation of Y654 77 . Tissue growth is determined not only by the rate of proliferation but also by the loss of cells from the tissue that is similarly under control of mechanical signals. Epithelial crowding and consequent mechanical compression were demonstrated to trigger epithelial extrusion, driving loss of both apoptotic and live cells from epithelial tissues 87 – 91 . The stretch-sensitive calcium channel Piezo1 was identified as the main responsible mechano-transducer in this process 87 . Since modulation of E-cadherin adhesions can trigger epithelial delamination 92 , 93 and the distribution of tensile forces on E-cadherin junctions has been implicated in apical extrusion of apoptotic cells 94 , 95 , it will be interesting to test whether mechanotransduction by E-cadherin junctions plays a role in density-dependent cell extrusion as well. Orienting cell divisions by intercellular forces Shaping of tissues can be directed by the orientation of cell divisions and subsequent positioning of daughter cells. Division orientation is specified by the position of the mitotic spindle, which is controlled by pulling forces on astral microtubules that link the mitotic spindle to the cell cortex 96 . Across metazoan species, including Xenopus , zebrafish, Drosophila , and mammals, it has been observed that epithelial divisions align with anisotropic tensile forces 97 – 100 . This serves to direct tissue elongation 65 , 100 , 101 and to dissipate high levels of anisotropic tissue tension that may arise during morphogenesis 97 , 98 , 101 . Initially, tension-oriented cell division was considered to be primarily a consequence of cell elongation along the tension axis 65 , 97 , 98 , 101 . This idea is supported by the “long axis rule”, postulated by Oscar Hertwig already in the late 19th century, stating that cells tend to divide along their longest axis. However, in epithelial monolayers, cell shape information is typically compromised by mitotic rounding. It was revealed in the Drosophila pupal notum how epithelial cells are able to preserve information of their interphase shape during mitosis 102 . Tricellular junctions (TCJs), specialized adhesions at sites where three (or more) cells meet, recruit microtubule force generators via the dynein-associated protein Mud. The distribution of TCJs aligns with cell shape and mechanical stress orientation within the tissue and this spatial information is retained upon mitotic rounding ( Figure 4 ) 102 . Future experiments may answer whether Mud recruitment to TCJs is mechanically controlled, as TCJs are sites of increased intercellular tension 103 . Similar to Drosophila , the Mud homologue NuMA is required for cell divisions to align with the direction of tension in stretched mammalian epithelia 104 . However, in contrast to Mud, NuMA is retained within the nucleus during interphase 105 – 107 . Instead, during interphase in mammalian epithelia, the NuMA-interacting protein LGN is recruited to E-cadherin junctions in a tension-dependent manner, thereby localizing in a polarized fashion under conditions of anisotropic junctional tension 25 . Following mitotic entry and nuclear breakdown, the E-cadherin/LGN complex directs the recruitment of NuMA to cell–cell adhesions and enables orientation of the mitotic spindle along the axis of tissue tension ( Figure 4 ). LGN competes for E-cadherin binding with p120-catenin 107 , 108 , which may underlie its force-dependent recruitment to cell–cell junctions as p120-catenin was recently shown to relocalize from cell–cell junctions to the cytosol upon increased intercellular tension 109 . Application of a low level of stretch to mammalian epithelial monolayers showed not only that force-dependent recruitment of LGN to E-cadherin is required to align divisions along the tension axis but also that this mechanism can overrule cell shape in determining division orientation 25 . Shape-uncoupled orientation of division by tissue tension was recently also shown in vivo in the Drosophila mesectoderm and follicle epithelium, in which cells divide preferentially along the direction of tissue expansion that is perpendicular to the interphase long axis 110 , 111 . In these cells, this occurs independently of either TCJs or LGN/NuMA and instead involves anisotropic remodeling of the actomyosin cytoskeleton and cortical mechanics that may affect the ability of force generators to exert forces on the mitotic spindle 110 , 111 . Because of the role of E-cadherin in force-dependent remodeling of junctional actin, it will be interesting to explore whether regulation of the actomyosin cytoskeleton contributes to the ability of E-cadherin to align cell divisions with anisotropic tensile forces. Figure 4. Regulation of cell division orientation by intercellular forces. In the Drosophila pupal notum (top panel), the dynein-associated protein Mud is recruited to tricellular junctions (TCJs) during the G 2 phase of the cell cycle. In this way, in mitosis TCJs form cortical anchor points for astral microtubules that generate dynein-dependent pulling forces to orient the mitotic spindle. The distribution of TCJs aligns with cell shape and mechanical stress orientations within the epithelium, which is preserved upon mitotic rounding. In mammalian and Xenopus laevis epithelia (bottom panel), the Mud homologue NuMA is retained within the nucleus during interphase. Instead, the NuMA-interacting protein LGN, which directly interacts with E-cadherin, is recruited to junctions that are under elevated tension, leading to its polarization in mechanically stretched epithelial monolayers. Following mitotic entry and nuclear breakdown, the E-cadherin/LGN complex directs the recruitment of NuMA to cell–cell adhesions and thereby aligns cell divisions with the tension axis, which can overrule the interphase long axis of the cell in orienting division. Although this is not directly apparent in mammalian epithelia 25 , 107 , LGN is enriched at TCJs in Xenopus epithelia 113 , implying that the tension-dependent recruitment of LGN by E-cadherin also provides a mechanism to align division with the position of TCJs. Mechanical forces underlying cell–cell intercalation In addition to being transmitted by AJs and transduced into an intracellular response, mechanical forces can regulate tissue shape by remodeling of cell–cell contacts through force-dependent regulation of AJ turnover 109 . This occurs most prominently during cell intercalation, which drives convergence of the tissue along one axis and extension along the orthogonal axis 112 . Cell rearrangements underlying intercalation are driven by shrinkage and disassembly of junctions perpendicular to the axis of extension, followed by formation of junctions with new neighbors. During Drosophila germband extension, shrinkage of dorsoventral junctions is controlled by polarized induction of actomyosin contractility 114 – 116 . The underlying increase in internalization of the cadherin complex in part involves Y667 phosphorylation of β-catenin (Y654 in mammals) 117 , 118 , an event that was recently shown to be directly regulated by tensile force 82 . A possible explanation of the opposite effects of myosin-generated tension on cadherin junctions, either junction shrinkage or junction reinforcement (discussed earlier), may lie in the force orientation with respect to the junction. During junction shrinkage, forces parallel to the cell–cell contact orientation result in shear stress on the junction complex, which decreases E-cadherin levels at the junction 119 . In contrast, force that is oriented perpendicular to anterior–posterior junctions was shown to increase junctional E-cadherin levels 119 . While E-cadherin levels decrease in shrinking junctions, the tension-sensitive recruitment of the actin regulators Vinculin, Ajuba, and AIP1 is increased, enabling the junction to cope with the elevated mechanical load 119 – 121 . After shrinkage of dorsoventral junctions, the germband extends upon resolving the intermediate multicellular vertices and elongation of anterior–posterior junctions. For AJs to withstand the high level of tension at multicellular vertices and for subsequent vertex resolution, the force-sensitive recruitment of Ajuba is essential 121 . Intriguingly, junction elongation does not happen merely as a result of tissue relaxation but instead is actively controlled by actomyosin activity as well 122 , 123 . Clearly, a dynamic interplay between mechanically controlled AJ turnover and strengthening is essential during intercalation, and future studies will likely provide more insights into the role of E-cadherin mechanotransduction in this. Future perspectives AJs have emerged as integral components in the regulation of morphogenesis by mechanical forces. In recent years, molecular details of cadherin mechanotransduction in morphogenetic processes of collective migration, cell division, and cell intercalation have started to be resolved. Future research will likely shed more light on how cadherin mechanotransduction impacts other processes that regulate tissue development and homeostasis, such as the control of cell shape, differentiation, and delamination 2 , 22 , 92 , 124 . Several important questions remain just at the start of investigation, for instance how cells discriminate between forces of different magnitudes and timescales. Different timescales add the conundrum that the short-term responses of cells to intercellular forces (for example, cell shape change or Vinculin recruitment to adhesion sites) function to dissipate force and therefore potentially prevent long-term responses 125 . Moreover, it remains unanswered whether different force-dependent constituents of the AJ can be present simultaneously within the same cadherin complex, and mutual exclusivity is likely to exist (for example, between proteins competing for α-catenin binding). Understanding how the different components of cadherin mechanotransduction may be responsive to distinct magnitudes and types of force 126 will further help to explain why cells may adopt different, sometimes opposing, mechano-responses through cadherin junctions (for example, junction reinforcement or junction remodeling). Although we have focused primarily on AJs, cell–cell contacts contain additional adhesion complexes (that is, tight junctions and desmosomes) that are exposed to external mechanical force 127 , adopt tension-sensitive changes in their composition 128 , and contribute to the transduction of intercellular forces 39 . Moreover, intercellular forces can be sensed by mechano-sensing complexes that respond to membrane deformations, a mechanism used by mechano-sensitive ion channels that adopt open and closed conformations depending on local force-induced membrane deformations 129 , 130 . So far, research on mechanotransduction has predominantly approached the various mechano-sensitive complexes as isolated units. To properly understand cellular responses to forces, it will be pivotal to know how they cooperate. Interplay further exists between AJs and mechano-sensitive complexes that are not localized at cell–cell contacts, such as focal adhesions that contain numerous mechano-sensitive components that are in part shared with the AJ 6 . Mechanotransduction by both adhesion complexes can converge on similar transcription factors and may cooperate in the activation of signaling pathways as has been shown for the activation of β-catenin 77 . In coming years, unraveling the interplay between these different mechano-sensitive complexes will be instrumental in understanding the variety of cellular behaviors that are controlled by mechanical force. Finally, it is becoming increasingly apparent that mechanical signals that cells receive from their environment continuously crosstalk with biochemical signals, such as growth factors and hormones. Not only can both impinge on the same intracellular signaling cascades, but several growth factor receptors are also directly (for example, Notch 131 , 132 ) or indirectly (for example, EGFR 21 and insulin receptor 133 ) regulated by mechanical force. Moreover, biochemical signaling pathways may feedback to modulate the cellular mechano-response 134 . A better comprehension of the dynamic interplay between mechanical and biochemical signaling will be imperative to understand the complexities of animal development. Grant information JdR is supported by the European Commission (H2020-FETPROACT-01-2016-731957), and MG is supported by the Netherlands Organisation for Scientific Research (NWO; 016.Vidi.189.166 and NWO gravitational program CancerGenomiCs.nl). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We thank Jooske Monster (UMC Utrecht, The Netherlands) for critical reading of the manuscript. Faculty Opinions recommended References 1. Stooke-Vaughan GA, Campàs O: Physical control of tissue morphogenesis across scales. Curr Opin Genet Dev. 2018; 51 : 111–9. PubMed Abstract | Publisher Full Text | Free Full Text 2. Vasquez CG, Martin AC: Force transmission in epithelial tissues. Dev Dyn. 2016; 245 (3): 361–71. PubMed Abstract | Publisher Full Text | Free Full Text 3. Iskratsch T, Wolfenson H, Sheetz MP: Appreciating force and shape—the rise of mechanotransduction in cell biology. Nat Rev Mol Cell Biol. 2014; 15 (12): 825–33. PubMed Abstract | Publisher Full Text 4. Ladoux B, Nelson WJ, Yan J, et al. : The mechanotransduction machinery at work at adherens junctions. Integr Biol (Camb). 2015; 7 (10): 1109–19. PubMed Abstract | Publisher Full Text | Free Full Text 5. Gasparski AN, Beningo KA: Mechanoreception at the cell membrane: More than the integrins. Arch Biochem Biophys. 2015; 586 : 20–6. PubMed Abstract | Publisher Full Text 6. Han MKL, de Rooij J: Converging and Unique Mechanisms of Mechanotransduction at Adhesion Sites. Trends Cell Biol. 2016; 26 (8): 612–23. PubMed Abstract | Publisher Full Text 7. Buckley CD, Tan J, Anderson KL, et al. : Cell adhesion. The minimal cadherin-catenin complex binds to actin filaments under force. Science. 2014; 346 (6209): 1254211. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 8. Ishiyama N, Sarpal R, Wood MN, et al. : Force-dependent allostery of the α-catenin actin-binding domain controls adherens junction dynamics and functions. Nat Commun. 2018; 9 (1): 5121. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 9. Yonemura S, Wada Y, Watanabe T, et al. : alpha-Catenin as a tension transducer that induces adherens junction development. Nat Cell Biol. 2010; 12 (6): 533–42. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 10. Thomas WA, Boscher C, Chu YS, et al. : α-Catenin and vinculin cooperate to promote high E-cadherin-based adhesion strength. J Biol Chem. 2013; 288 (7): 4957–69. PubMed Abstract | Publisher Full Text | Free Full Text 11. le Duc Q, Shi Q, Blonk I, et al. : Vinculin potentiates E-cadherin mechanosensing and is recruited to actin-anchored sites within adherens junctions in a myosin II-dependent manner. J Cell Biol. 2010; 189 (7): 1107–15. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 12. Yao M, Qiu W, Liu R, et al. : Force-dependent conformational switch of α-catenin controls vinculin binding. Nat Commun. 2014; 5 : 4525. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 13. Leerberg JM, Gomez GA, Verma S, et al. : Tension-sensitive actin assembly supports contractility at the epithelial zonula adherens. Curr Biol. 2014; 24 (15): 1689–99. PubMed Abstract | Publisher Full Text | Free Full Text 14. Ito S, Okuda S, Abe M, et al. : Induced cortical tension restores functional junctions in adhesion-defective carcinoma cells. Nat Commun. 2017; 8 (1): 1834. PubMed Abstract | Publisher Full Text | Free Full Text 15. Huang DL, Bax NA, Buckley CD, et al. : Vinculin forms a directionally asymmetric catch bond with F-actin. Science. 2017; 357 (6352): 703–6. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 16. Matsuzawa K, Himoto T, Mochizuki Y, et al. : α-Catenin Controls the Anisotropy of Force Distribution at Cell-Cell Junctions during Collective Cell Migration. Cell Rep. 2018; 23 (12): 3447–56. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 17. Acharya BR, Nestor-Bergmann A, Liang X, et al. : A Mechanosensitive RhoA Pathway that Protects Epithelia against Acute Tensile Stress. Dev Cell. 2018; 47 (4): 439–452.e6. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 18. Oldenburg J, van der Krogt G, Twiss F, et al. : VASP, zyxin and TES are tension-dependent members of Focal Adherens Junctions independent of the α-catenin-vinculin module. Sci Rep. 2015; 5 : 17225. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 19. Han MKL, van der Krogt GNM, de Rooij J: Zygotic vinculin is not essential for embryonic development in zebrafish. PLoS One. 2017; 12 (8): e0182278. PubMed Abstract | Publisher Full Text | Free Full Text 20. Alatortsev VE, Kramerova IA, Frolov MV, et al. : Vinculin gene is non-essential in Drosophila melanogaster . FEBS Lett. 1997; 413 (2): 197–201. PubMed Abstract | Publisher Full Text 21. Rübsam M, Mertz AF, Kubo A, et al. : E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning. Nat Commun. 2017; 8 (1): 1250. PubMed Abstract | Publisher Full Text | Free Full Text 22. Fernandez-Sanchez ME, Brunet T, Röper JC, et al. : Mechanotransduction's impact on animal development, evolution, and tumorigenesis. Annu Rev Cell Dev Biol. 2015; 31 : 373–97. PubMed Abstract | Publisher Full Text 23. Mitrossilis D, Röper JC, Le Roy D, et al. : Mechanotransductive cascade of Myo-II-dependent mesoderm and endoderm invaginations in embryo gastrulation. Nat Commun. 2017; 8 : 13883. PubMed Abstract | Publisher Full Text | Free Full Text 24. Benham-Pyle BW, Pruitt BL, Nelson WJ: Cell adhesion. Mechanical strain induces E-cadherin-dependent Yap1 and β-catenin activation to drive cell cycle entry. Science. 2015; 348 (6238): 1024–7. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 25. Hart KC, Tan J, Siemers KA, et al. : E-cadherin and LGN align epithelial cell divisions with tissue tension independently of cell shape. Proc Natl Acad Sci U S A. 2017; 114 (29): E5845–E5853. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 26. Weber GF, Bjerke MA, DeSimone DW: A mechanoresponsive cadherin-keratin complex directs polarized protrusive behavior and collective cell migration. Dev Cell. 2012; 22 (1): 104–15. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 27. Cai D, Chen SC, Prasad M, et al. : Mechanical feedback through E-cadherin promotes direction sensing during collective cell migration. Cell. 2014; 157 (5): 1146–59. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 28. Bays JL, Campbell HK, Heidema C, et al. : Linking E-cadherin mechanotransduction to cell metabolism through force-mediated activation of AMPK. Nat Cell Biol. 2017; 19 (6): 724–31. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 29. Fernández-Sánchez ME, Barbier S, Whitehead J, et al. : Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure. Nature. 2015; 523 (7558): 92–5. PubMed Abstract | Publisher Full Text 30. Mayor R, Etienne-Manneville S: The front and rear of collective cell migration. Nat Rev Mol Cell Biol. 2016; 17 (2): 97–109. PubMed Abstract | Publisher Full Text 31. Sunyer R, Conte V, Escribano J, et al. : Collective cell durotaxis emerges from long-range intercellular force transmission. Science. 2016; 353 (6304): 1157–61. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 32. Barriga EH, Franze K, Charras G, et al. : Tissue stiffening coordinates morphogenesis by triggering collective cell migration in vivo . Nature. 2018; 554 (7693): 523–7. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 33. Vedula SR, Leong MC, Lai TL, et al. : Emerging modes of collective cell migration induced by geometrical constraints. Proc Natl Acad Sci U S A. 2012; 109 (32): 12974–9. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 34. Ladoux B, Mège RM, Trepat X: Front-Rear Polarization by Mechanical Cues: From Single Cells to Tissues. Trends Cell Biol. 2016; 26 (6): 420–33. PubMed Abstract | Publisher Full Text | Free Full Text 35. Ladoux B, Mège RM: Mechanobiology of collective cell behaviours. Nat Rev Mol Cell Biol. 2017; 18 (12): 743–57. PubMed Abstract | Publisher Full Text 36. Trepat X, Wasserman MR, Angelini TE, et al. : Physical forces during collective cell migration. Nat Phys. 2009; 5 : 426–30. Publisher Full Text | Faculty Opinions Recommendation 37. Rakshit S, Zhang Y, Manibog K, et al. : Ideal, catch, and slip bonds in cadherin adhesion. Proc Natl Acad Sci U S A. 2012; 109 (46): 18815–20. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 38. Tambe DT, Hardin CC, Angelini TE, et al. : Collective cell guidance by cooperative intercellular forces. Nat Mater. 2011; 10 (6): 469–75. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 39. Bazellières E, Conte V, Elosegui-Artola A, et al. : Control of cell-cell forces and collective cell dynamics by the intercellular adhesome. Nat Cell Biol. 2015; 17 (4): 409–20. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 40. Trepat X, Fredberg JJ: Plithotaxis and emergent dynamics in collective cellular migration. Trends Cell Biol. 2011; 21 (11): 638–46. PubMed Abstract | Publisher Full Text | Free Full Text 41. Seddiki R, Narayana GHNS, Strale PO, et al. : Force-dependent binding of vinculin to α-catenin regulates cell-cell contact stability and collective cell behavior. Mol Biol Cell. 2018; 29 (4): 380–8. PubMed Abstract | Publisher Full Text | Free Full Text 42. Han MK, Hoijman E, Nöel E, et al. : αE-catenin-dependent mechanotransduction is essential for proper convergent extension in zebrafish. Biol Open. 2016; 5 (10): 1461–72. PubMed Abstract | Publisher Full Text | Free Full Text 43. Zegers MM, Friedl P: Rho GTPases in collective cell migration. Small GTPases. 2014; 5 : e28997. PubMed Abstract | Publisher Full Text | Free Full Text 44. Das T, Safferling K, Rausch S, et al. : A molecular mechanotransduction pathway regulates collective migration of epithelial cells. Nat Cell Biol. 2015; 17 (3): 276–87. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 45. Furukawa KT, Yamashita K, Sakurai N, et al. : The Epithelial Circumferential Actin Belt Regulates YAP/TAZ through Nucleocytoplasmic Shuttling of Merlin. Cell Rep. 2017; 20 (6): 1435–47. PubMed Abstract | Publisher Full Text 46. Plutoni C, Bazellieres E, Le Borgne-Rochet M, et al. : P-cadherin promotes collective cell migration via a Cdc42-mediated increase in mechanical forces. J Cell Biol. 2016; 212 (2): 199–217. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 47. Hayer A, Shao L, Chung M, et al. : Engulfed cadherin fingers are polarized junctional structures between collectively migrating endothelial cells. Nat Cell Biol. 2016; 18 (12): 1311–23. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 48. Aspenström P: BAR Domain Proteins Regulate Rho GTPase Signaling. Adv Exp Med Biol. 2018. PubMed Abstract | Publisher Full Text 49. Malinova TS, Huveneers S: Sensing of Cytoskeletal Forces by Asymmetric Adherens Junctions. Trends Cell Biol. 2018; 28 (4): 328–41. PubMed Abstract | Publisher Full Text 50. Khalil AA, Friedl P: Determinants of leader cells in collective cell migration. Integr Biol (Camb). 2010; 2 (11–12): 568–74. PubMed Abstract | Publisher Full Text 51. Khalil AA, de Rooij J: Cadherin mechanotransduction in leader-follower cell specification during collective migration. Exp Cell Res. 2019; 376 (1): 86–91. PubMed Abstract | Publisher Full Text 52. Vishwakarma M, Di Russo J, Probst D, et al. : Mechanical interactions among followers determine the emergence of leaders in migrating epithelial cell collectives. Nat Commun. 2018; 9 (1): 3469. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 53. Shellard A, Szabó A, Trepat X, et al. : Supracellular contraction at the rear of neural crest cell groups drives collective chemotaxis. Science. 2018; 362 (6412): 339–43. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 54. Nelson CM, Jean RP, Tan JL, et al. : Emergent patterns of growth controlled by multicellular form and mechanics. Proc Natl Acad Sci U S A. 2005; 102 (33): 11594–9. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 55. Mohan A, Schlue KT, Kniffin AF, et al. : Spatial Proliferation of Epithelial Cells Is Regulated by E-Cadherin Force. Biophys J. 2018; 115 (5): 853–64. PubMed Abstract | Publisher Full Text | Free Full Text 56. Uroz M, Wistorf S, Serra-Picamal X, et al. : Regulation of cell cycle progression by cell-cell and cell-matrix forces. Nat Cell Biol. 2018; 20 (6): 646–54. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 57. Rauskolb C, Sun S, Sun G, et al. : Cytoskeletal tension inhibits Hippo signaling through an Ajuba-Warts complex. Cell. 2014; 158 (1): 143–56. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 58. Puliafito A, Hufnagel L, Neveu P, et al. : Collective and single cell behavior in epithelial contact inhibition. Proc Natl Acad Sci U S A. 2012; 109 (3): 739–44. PubMed Abstract | Publisher Full Text | Free Full Text 59. Aragona M, Panciera T, Manfrin A, et al. : A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell. 2013; 154 (5): 1047–59. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 60. Streichan SJ, Hoerner CR, Schneidt T, et al. : Spatial constraints control cell proliferation in tissues. Proc Natl Acad Sci U S A. 2014; 111 (15): 5586–91. PubMed Abstract | Publisher Full Text | Free Full Text 61. Codelia VA, Sun G, Irvine KD: Regulation of YAP by mechanical strain through Jnk and Hippo signaling. Curr Biol. 2014; 24 (17): 2012–7. PubMed Abstract | Publisher Full Text | Free Full Text 62. Schluck T, Nienhaus U, Aegerter-Wilmsen T, et al. : Mechanical control of organ size in the development of the Drosophila wing disc. PLoS One. 2013; 8 (10): e76171. PubMed Abstract | Publisher Full Text | Free Full Text 63. Gudipaty SA, Lindblom J, Loftus PD, et al. : Mechanical stretch triggers rapid epithelial cell division through Piezo1. Nature. 2017; 543 (7643): 118–21. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 64. Alégot H, Markosian C, Rauskolb C, et al. : Recruitment of Jub by α-catenin promotes Yki activity and Drosophila wing growth. J Cell Sci. 2019; 132 (5): pii: jcs222018. PubMed Abstract | Publisher Full Text | Free Full Text 65. Mao Y, Tournier AL, Hoppe A, et al. : Differential proliferation rates generate patterns of mechanical tension that orient tissue growth. EMBO J. 2013; 32 (21): 2790–803. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 66. Pan Y, Heemskerk I, Ibar C, et al. : Differential growth triggers mechanical feedback that elevates Hippo signaling. Proc Natl Acad Sci U S A. 2016; 113 (45): E6974–E6983. PubMed Abstract | Publisher Full Text | Free Full Text 67. Li Q, Nirala NK, Nie Y, et al. : Ingestion of Food Particles Regulates the Mechanosensing Misshapen-Yorkie Pathway in Drosophila Intestinal Growth. Dev Cell. 2018; 45 (4): 433–449.e6. PubMed Abstract | Publisher Full Text 68. He L, Si G, Huang J, et al. : Mechanical regulation of stem-cell differentiation by the stretch-activated Piezo channel. Nature. 2018; 555 (7694): 103–6. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 69. McClatchey AI, Yap AS: Contact inhibition (of proliferation) redux. Curr Opin Cell Biol. 2012; 24 (5): 685–94. PubMed Abstract | Publisher Full Text 70. Kim NG, Koh E, Chen X, et al. : E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc Natl Acad Sci U S A. 2011; 108 (29): 11930–5. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 71. Mendonsa AM, Na TY, Gumbiner BM: E-cadherin in contact inhibition and cancer. Oncogene. 2018; 37 (35): 4769–80. PubMed Abstract | Publisher Full Text | Free Full Text 72. Dutta S, Mana-Capelli S, Paramasivam M, et al. : TRIP6 inhibits Hippo signaling in response to tension at adherens junctions. EMBO Rep. 2018; 19 (2): 337–50. PubMed Abstract | Publisher Full Text | Free Full Text 73. Ibar C, Kirichenko E, Keepers B, et al. : Tension-dependent regulation of mammalian Hippo signaling through LIMD1. J Cell Sci. 2018; 131 (5): pii: jcs214700. PubMed Abstract | Publisher Full Text | Free Full Text 74. Schlegelmilch K, Mohseni M, Kirak O, et al. : Yap1 acts downstream of α-catenin to control epidermal proliferation. Cell. 2011; 144 (5): 782–95. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 75. Giampietro C, Disanza A, Bravi L, et al. : The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling. J Cell Biol. 2015; 211 (6): 1177–92. PubMed Abstract | Publisher Full Text | Free Full Text 76. Elosegui-Artola A, Andreu I, Beedle AEM, et al. : Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores. Cell. 2017; 171 (6): 1397–1410.e14. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 77. Gayrard C, Bernaudin C, Déjardin T, et al. : Src- and confinement-dependent FAK activation causes E-cadherin relaxation and β-catenin activity. J Cell Biol. 2018; 217 (3): 1063–77. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 78. Mateus R, Lourenco R, Fang Y, et al. : Control of tissue growth by Yap relies on cell density and F-actin in zebrafish fin regeneration. Development. 2015; 142 (16): 2752–63. PubMed Abstract | Publisher Full Text | Free Full Text 79. Muhamed I, Wu J, Sehgal P, et al. : E-cadherin-mediated force transduction signals regulate global cell mechanics. J Cell Sci. 2016; 129 (9): 1843–54. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 80. Chiasson-MacKenzie C, Morris ZS, Baca Q, et al. : NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin. J Cell Biol. 2015; 211 (2): 391–405. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 81. Benham-Pyle BW, Sim JY, Hart KC, et al. : Increasing β-catenin/Wnt3A activity levels drive mechanical strain-induced cell cycle progression through mitosis. eLife. 2016; 5 : pii: e19799. PubMed Abstract | Publisher Full Text | Free Full Text 82. Röper JC, Mitrossilis D, Stirnemann G, et al. : The major β-catenin/E-cadherin junctional binding site is a primary molecular mechano-transductor of differentiation in vivo . eLife. 2018; 7 : pii: e33381. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 83. Brunet T, Bouclet A, Ahmadi P, et al. : Evolutionary conservation of early mesoderm specification by mechanotransduction in Bilateria. Nat Commun. 2013; 4 : 2821. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 84. Desprat N, Supatto W, Pouille PA, et al. : Tissue deformation modulates twist expression to determine anterior midgut differentiation in Drosophila embryos. Dev Cell. 2008; 15 (3): 470–7. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 85. Shyer AE, Rodrigues AR, Schroeder GG, et al. : Emergent cellular self-organization and mechanosensation initiate follicle pattern in the avian skin. Science. 2017; 357 (6353): 811–5. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 86. Zhu J, Thompson CB: Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Biol. 2019; 20 (7): 436–450. PubMed Abstract | Publisher Full Text | Free Full Text 87. Eisenhoffer GT, Loftus PD, Yoshigi M, et al. : Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia. Nature. 2012; 484 (7395): 546–9. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 88. Marinari E, Mehonic A, Curran S, et al. : Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding. Nature. 2012; 484 (7395): 542–5. PubMed Abstract | Publisher Full Text 89. Saw TB, Doostmohammadi A, Nier V, et al. : Topological defects in epithelia govern cell death and extrusion. Nature. 2017; 544 (7649): 212–6. PubMed Abstract | Publisher Full Text | Free Full Text 90. Moreno E, Valon L, Levillayer F, et al. : Competition for Space Induces Cell Elimination through Compaction-Driven ERK Downregulation. Curr Biol. 2019; 29 (1): 23–34.e8. PubMed Abstract | Publisher Full Text | Free Full Text 91. Kocgozlu L, Saw TB, Le AP, et al. : Epithelial Cell Packing Induces Distinct Modes of Cell Extrusions. Curr Biol. 2016; 26 (21): 2942–50. PubMed Abstract | Publisher Full Text | Free Full Text 92. Miroshnikova YA, Le HQ, Schneider D, et al. : Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification. Nat Cell Biol. 2018; 20 (1): 69–80. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 93. Grieve AG, Rabouille C: Extracellular cleavage of E-cadherin promotes epithelial cell extrusion. J Cell Sci. 2014; 127 (Pt 15): 3331–46. PubMed Abstract | Publisher Full Text 94. Michael M, Meiring JCM, Acharya BR, et al. : Coronin 1B Reorganizes the Architecture of F-Actin Networks for Contractility at Steady-State and Apoptotic Adherens Junctions. Dev Cell. 2016; 37 (1): 58–71. PubMed Abstract | Publisher Full Text 95. Wu SK, Gomez GA, Michael M, et al. : Cortical F-actin stabilization generates apical-lateral patterns of junctional contractility that integrate cells into epithelia. Nat Cell Biol. 2014; 16 (2): 167–78. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 96. di Pietro F, Echard A, Morin X: Regulation of mitotic spindle orientation: an integrated view. EMBO Rep. 2016; 17 (8): 1106–30. PubMed Abstract | Publisher Full Text | Free Full Text 97. Campinho P, Behrndt M, Ranft J, et al. : Tension-oriented cell divisions limit anisotropic tissue tension in epithelial spreading during zebrafish epiboly. Nat Cell Biol. 2013; 15 (12): 1405–14. PubMed Abstract | Publisher Full Text 98. Legoff L, Rouault H, Lecuit T: A global pattern of mechanical stress polarizes cell divisions and cell shape in the growing Drosophila wing disc. Development. 2013; 140 (19): 4051–9. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 99. Petridou NI, Skourides PA: FAK transduces extracellular forces that orient the mitotic spindle and control tissue morphogenesis. Nat Commun. 2014; 5 : 5240. PubMed Abstract | Publisher Full Text 100. Wang MF, Hunter MV, Wang G, et al. : Automated cell tracking identifies mechanically oriented cell divisions during Drosophila axis elongation. Development. 2017; 144 (7): 1350–61. PubMed Abstract | Publisher Full Text 101. Wyatt TP, Harris AR, Lam M, et al. : Emergence of homeostatic epithelial packing and stress dissipation through divisions oriented along the long cell axis. Proc Natl Acad Sci U S A. 2015; 112 (18): 5726–31. PubMed Abstract | Publisher Full Text | Free Full Text 102. Bosveld F, Markova O, Guirao B, et al. : Epithelial tricellular junctions act as interphase cell shape sensors to orient mitosis. Nature. 2016; 530 (7591): 495–8. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 103. Higashi T, Miller AL: Tricellular junctions: how to build junctions at the TRICkiest points of epithelial cells. Mol Biol Cell. 2017; 28 (15): 2023–34. PubMed Abstract | Publisher Full Text | Free Full Text 104. Seldin L, Poulson ND, Foote HP, et al. : NuMA localization, stability, and function in spindle orientation involve 4.1 and Cdk1 interactions. Mol Biol Cell. 2013; 24 (23): 3651–62. PubMed Abstract | Publisher Full Text | Free Full Text 105. Tang Z, Hu Y, Wang Z, et al. : Mechanical Forces Program the Orientation of Cell Division during Airway Tube Morphogenesis. Dev Cell. 2018; 44 (3): 313–325.e5. PubMed Abstract | Publisher Full Text 106. Radulescu AE, Cleveland DW: NuMA after 30 years: the matrix revisited. Trends Cell Biol. 2010; 20 (4): 214–22. PubMed Abstract | Publisher Full Text | Free Full Text 107. Gloerich M, Bianchini JM, Siemers KA, et al. : Cell division orientation is coupled to cell-cell adhesion by the E-cadherin/LGN complex. Nat Commun. 2017; 8 : 13996. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 108. Conway DE, Coon BG, Budatha M, et al. : VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN. Curr Biol. 2017; 27 (14): 2219–2225.e5. PubMed Abstract | Publisher Full Text | Free Full Text 109. Iyer KV, Piscitello-Gómez R, Paijmans J, et al. : Epithelial Viscoelasticity Is Regulated by Mechanosensitive E-cadherin Turnover. Curr Biol. 2019; 29 (4): 578–591.e5. PubMed Abstract | Publisher Full Text 110. Finegan TM, Na D, Cammarota C, et al. : Tissue tension and not interphase cell shape determines cell division orientation in the Drosophila follicular epithelium. EMBO J. 2019; 38 (3): pii: e100072. PubMed Abstract | Publisher Full Text | Free Full Text 111. Scarpa E, Finet C, Blanchard GB, et al. : Actomyosin-Driven Tension at Compartmental Boundaries Orients Cell Division Independently of Cell Geometry In Vivo . Dev Cell. 2018; 47 (6): 727–740.e6. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 112. Tada M, Heisenberg CP: Convergent extension: using collective cell migration and cell intercalation to shape embryos. Development. 2012; 139 (21): 3897–904. PubMed Abstract | Publisher Full Text 113. Nestor-Bergmann A, Stooke-Vaughan GA, Goddard GK, et al. : Decoupling the Roles of Cell Shape and Mechanical Stress in Orienting and Cueing Epithelial Mitosis. Cell Rep. 2019; 26 (8): 2088–2100.e4. PubMed Abstract | Publisher Full Text | Free Full Text 114. Bertet C, Sulak L, Lecuit T: Myosin-dependent junction remodelling controls planar cell intercalation and axis elongation. Nature. 2004; 429 (6992): 667–71. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 115. Fernandez-Gonzalez R, Simoes Sde M, Röper JC, et al. : Myosin II dynamics are regulated by tension in intercalating cells. Dev Cell. 2009; 17 (5): 736–43. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 116. Rauzi M, Lenne PF, Lecuit T: Planar polarized actomyosin contractile flows control epithelial junction remodelling. Nature. 2010; 468 (7327): 1110–4. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 117. Levayer R, Pelissier-Monier A, Lecuit T: Spatial regulation of Dia and Myosin-II by RhoGEF2 controls initiation of E-cadherin endocytosis during epithelial morphogenesis. Nat Cell Biol. 2011; 13 (5): 529–40. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 118. Tamada M, Farrell DL, Zallen JA: Abl regulates planar polarized junctional dynamics through β-catenin tyrosine phosphorylation. Dev Cell. 2012; 22 (2): 309–19. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 119. Kale GR, Yang X, Philippe JM, et al. : Distinct contributions of tensile and shear stress on E-cadherin levels during morphogenesis. Nat Commun. 2018; 9 (1): 5021. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 120. Ikawa K, Sugimura K: AIP1 and cofilin ensure a resistance to tissue tension and promote directional cell rearrangement. Nat Commun. 2018; 9 (1): 3295. PubMed Abstract | Publisher Full Text | Free Full Text 121. Razzell W, Bustillo ME, Zallen JA: The force-sensitive protein Ajuba regulates cell adhesion during epithelial morphogenesis. J Cell Biol. 2018; 217 (10): 3715–30. PubMed Abstract | Publisher Full Text | Free Full Text 122. Collinet C, Rauzi M, Lenne PF, et al. : Local and tissue-scale forces drive oriented junction growth during tissue extension. Nat Cell Biol. 2015; 17 (10): 1247–58. PubMed Abstract | Publisher Full Text 123. Yu JC, Fernandez-Gonzalez R: Local mechanical forces promote polarized junctional assembly and axis elongation in Drosophila . eLife. 2016; 5 : pii: e10757. PubMed Abstract | Publisher Full Text | Free Full Text 124. Wu SK, Lagendijk AK, Hogan BM, et al. : Active contractility at E-cadherin junctions and its implications for cell extrusion in cancer. Cell Cycle. 2015; 14 (3): 315–22. PubMed Abstract | Publisher Full Text | Free Full Text 125. Wyatt T, Baum B, Charras G: A question of time: tissue adaptation to mechanical forces. Curr Opin Cell Biol. 2016; 38 : 68–73. PubMed Abstract | Publisher Full Text 126. Charras G, Yap AS: Tensile Forces and Mechanotransduction at Cell-Cell Junctions. Curr Biol. 2018; 28 (8): R445–R457. PubMed Abstract | Publisher Full Text 127. Price AJ, Cost AL, Ungewiß H, et al. : Mechanical loading of desmosomes depends on the magnitude and orientation of external stress. Nat Commun. 2018; 9 (1): 5284. PubMed Abstract | Publisher Full Text | Free Full Text 128. Spadaro D, Le S, Laroche T, et al. : Tension-Dependent Stretching Activates ZO-1 to Control the Junctional Localization of Its Interactors. Curr Biol. 2017; 27 (24): 3783–3795.e8. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 129. Saotome K, Murthy SE, Kefauver JM, et al. : Structure of the mechanically activated ion channel Piezo1. Nature. 2018; 554 (7693): 481–6. PubMed Abstract | Publisher Full Text | Free Full Text 130. Zhao Q, Zhou H, Chi S, et al. : Structure and mechanogating mechanism of the Piezo1 channel. Nature. 2018; 554 (7693): 487–92. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 131. Gordon WR, Zimmerman B, He L, et al. : Mechanical Allostery: Evidence for a Force Requirement in the Proteolytic Activation of Notch. Dev Cell. 2015; 33 (6): 729–36. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 132. Luca VC, Kim BC, Ge C, et al. : Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity. Science. 2017; 355 (6331): 1320–4. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 133. Kim J, Bilder D, Neufeld TP: Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization. Genes Dev. 2018; 32 (2): 156–64. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 134. Sehgal P, Kong X, Wu J, et al. : Epidermal growth factor receptor and integrins control force-dependent vinculin recruitment to E-cadherin junctions. J Cell Sci. 2018; 131 (6): pii: jcs206656. PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 10 Jul 2019 ADD YOUR COMMENT Comment Author details Author details 1 Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands Willem-Jan Pannekoek Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing Johan de Rooij Roles: Writing – Review & Editing Martijn Gloerich Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information JdR is supported by the European Commission (H2020-FETPROACT-01-2016-731957), and MG is supported by the Netherlands Organisation for Scientific Research (NWO; 016.Vidi.189.166 and NWO gravitational program CancerGenomiCs.nl). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (1) version 1 Published: 10 Jul 2019, 8:1044 https://doi.org/10.12688/f1000research.18779.1 Copyright © 2019 Pannekoek WJ et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Pannekoek WJ, de Rooij J and Gloerich M. Force transduction by cadherin adhesions in morphogenesis [version 1; peer review: 3 approved] . F1000Research 2019, 8 (F1000 Faculty Rev):1044 ( https://doi.org/10.12688/f1000research.18779.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Editorial Note on the Review Process Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Reviewers who approved this article René-Marc Mège , Institut Jacques Monod, France Competing interests: No competing interests were declared. (for version 1) Emmanuel Farge , Mechanics and Genetics of Embryonic and Tumoral Development, Inserm, UMR 168 Physico-Chimie Curie Cnrs, Institut Curie - Paris Sciences et Lettres Research University, France Competing interests: No competing interests were declared. (for version 1) Carien Niessen , Department of Dermatology, CECAD Cologne and Center for Molecular Medicine Cologne, University of Cologne, Germany Competing interests: No competing interests were declared. (for version 1) Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 10 Jul 2019 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 1 10 Jul 19 Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. René-Marc Mège , Institut Jacques Monod, France Competing interests: No competing interests were declared. View more View less Emmanuel Farge , Mechanics and Genetics of Embryonic and Tumoral Development, Inserm, UMR 168 Physico-Chimie Curie Cnrs, Institut Curie - Paris Sciences et Lettres Research University, France Competing interests: No competing interests were declared. View more View less Carien Niessen , Department of Dermatology, CECAD Cologne and Center for Molecular Medicine Cologne, University of Cologne, Germany Competing interests: No competing interests were declared. View more View less Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Stay Updated Sign up for content alerts and receive a weekly or monthly email with all newly published articles Register with F1000Research Already registered? Sign in Not now, thanks close PLEASE NOTE If you are an AUTHOR of this article, please check that you signed in with the account associated with this article otherwise we cannot automatically identify your role as an author and your comment will be labelled as a “User Comment”. If you are a REVIEWER of this article, please check that you have signed in with the account associated with this article and then go to your account to submit your report, please do not post your review here. If you do not have access to your original account, please contact us . All commenters must hold a formal affiliation as per our Policies . The information that you give us will be displayed next to your comment. User comments must be in English, comprehensible and relevant to the article under discussion. We reserve the right to remove any comments that we consider to be inappropriate, offensive or otherwise in breach of the User Comment Terms and Conditions . Commenters must not use a comment for personal attacks. When criticisms of the article are based on unpublished data, the data should be made available. I accept the User Comment Terms and Conditions Please confirm that you accept the User Comment Terms and Conditions. Affiliation ✕ refresh Please enter your institution. Note: To add your institution or organisation, start typing the name and then select the correct name from the list. Where applicable, the name will appear in both the original language and in English. Do not paste in the name. If the name does not appear in the drop-down list, we will display the information you have entered. ✕ refresh Country/Region * USA UK Canada China France Germany Afghanistan Aland Islands Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory British Virgin Islands Brunei Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Cook Islands Costa Rica Cote d'Ivoire Croatia Cuba Cyprus Czech Republic Democratic Republic of the Congo Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Federated States of Micronesia Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and Mcdonald Islands Holy See (Vatican City State) Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati Kosovo (Serbia and Montenegro) Kuwait Kyrgyzstan Lao People's Democratic Republic Latvia Lebanon Lesotho Liberia Libya Liechtenstein Lithuania Luxembourg Macao Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Minor Outlying Islands of the United States Moldova Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island North Korea North Macedonia Northern Mariana Islands Norway Oman Pakistan Palau Palestinian Territory Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Puerto Rico Qatar Reunion Romania Russian Federation Rwanda Saint Helena Saint Kitts and Nevis Saint Lucia Saint Pierre and Miquelon Saint Vincent and the Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and the South Sandwich Is South Korea South Sudan Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syria Taiwan Tajikistan Tanzania Thailand The Gambia The Netherlands Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu UK USA Uganda Ukraine United Arab Emirates United States Virgin Islands Uruguay Uzbekistan Vanuatu Venezuela Vietnam Wallis and Futuna West Bank and Gaza Strip Western Sahara Yemen Zambia Zimbabwe Please select your country/region. You must enter a comment. Competing Interests Please disclose any competing interests that might be construed to influence your judgment of the article's or peer review report's validity or importance. Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Please state your competing interests The comment has been saved. An error has occurred. Please try again. Cancel Post var lTitle = "Force transduction by cadherin adhesions...".replace("'", ''); var linkedInUrl = "http://www.linkedin.com/shareArticle?url=https://f1000research.com/articles/8-1044/v1" + "&title=" + encodeURIComponent(lTitle) + "&summary=" + encodeURIComponent('Read the article by '); var deliciousUrl = "https://del.icio.us/post?url=https://f1000research.com/articles/8-1044/v1&title=" + encodeURIComponent(lTitle); var redditUrl = "http://reddit.com/submit?url=https://f1000research.com/articles/8-1044/v1" + "&title=" + encodeURIComponent(lTitle); linkedInUrl += encodeURIComponent('Pannekoek WJ et al.'); var offsetTop = /chrome/i.test( navigator.userAgent ) ? 4 : -10; var addthis_config = { ui_offset_top: offsetTop, services_compact : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_expanded : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_custom : [ { name: "LinkedIn", url: linkedInUrl, icon:"/img/icon/at_linkedin.svg" }, { name: "Mendeley", url: "http://www.mendeley.com/import/?url=https://f1000research.com/articles/8-1044/v1/mendeley", icon:"/img/icon/at_mendeley.svg" }, { name: "Reddit", url: redditUrl, icon:"/img/icon/at_reddit.svg" }, ] }; var addthis_share = { url: "https://f1000research.com/articles/8-1044", templates : { twitter : "Force transduction by cadherin adhesions in morphogenesis. Pannekoek WJ et al., published by " + "@F1000Research" + ", https://f1000research.com/articles/8-1044/v1" } }; if (typeof(addthis) != "undefined"){ addthis.addEventListener('addthis.ready', checkCount); addthis.addEventListener('addthis.menu.share', checkCount); } $(".f1r-shares-twitter").attr("href", "https://twitter.com/intent/tweet?text=" + addthis_share.templates.twitter); $(".f1r-shares-facebook").attr("href", "https://www.facebook.com/sharer/sharer.php?u=" + addthis_share.url); $(".f1r-shares-linkedin").attr("href", addthis_config.services_custom[0].url); $(".f1r-shares-reddit").attr("href", addthis_config.services_custom[2].url); $(".f1r-shares-mendelay").attr("href", addthis_config.services_custom[1].url); function checkCount(){ setTimeout(function(){ $(".addthis_button_expanded").each(function(){ var count = $(this).text(); if (count !== "" && count != "0") $(this).removeClass("is-hidden"); else $(this).addClass("is-hidden"); }); }, 1000); } close How to cite this report {{reportCitation}} Cancel Copy Citation Details $(function(){R.ui.buttonDropdowns('.dropdown-for-downloads');}); $(function(){R.ui.toolbarDropdowns('.toolbar-dropdown-for-downloads');}); $.get("/articles/acj/18779/20573") new F1000.Clipboard(); new F1000.ThesaurusTermsDisplay("faculty-reviews", "article", "20573"); $(document).ready(function() { $( "#frame1" ).on('load', function() { var mydiv = $(this).contents().find("div"); var h = mydiv.height(); console.log(h) }); var tooltipLivingFigure = jQuery(".interactive-living-figure-label .icon-more-info"), titleLivingFigure = tooltipLivingFigure.attr("title"); tooltipLivingFigure.simpletip({ fixed: true, position: ["-115", "30"], baseClass: 'small-tooltip', content:titleLivingFigure + " " }); tooltipLivingFigure.removeAttr("title"); $("body").on("click", ".cite-living-figure", function(e) { e.preventDefault(); var ref = $(this).attr("data-ref"); $(this).closest(".living-figure-list-container").find("#" + ref).fadeIn(200); }); $("body").on("click", ".close-cite-living-figure", function(e) { e.preventDefault(); $(this).closest(".popup-window-wrapper").fadeOut(200); }); $(document).on("mouseup", function(e) { var metricsContainer = $(".article-metrics-popover-wrapper"); if (!metricsContainer.is(e.target) && metricsContainer.has(e.target).length === 0) { $(".article-metrics-close-button").click(); } }); var articleId = $('#articleId').val(); if($("#main-article-count-box").attachArticleMetrics) { $("#main-article-count-box").attachArticleMetrics(articleId, { articleMetricsView: true }); } }); var figshareWidget = $(".new_figshare_widget"); if (figshareWidget.length > 0) { window.figshare.load("f1000", function(Widget) { // Select a tag/tags defined in your page. In this tag we will place the widget. _.map(figshareWidget, function(el){ var widget = new Widget({ articleId: $(el).attr("figshare_articleId") //height:300 // this is the height of the viewer part. [Default: 550] }); widget.initialize(); // initialize the widget widget.mount(el); // mount it in a tag that's on your page // this will save the widget on the global scope for later use from // your JS scripts. This line is optional. //window.widget = widget; }); }); } close Error Close Add Reset F1000.MICROSERVICES.AFFILIATION = ''; $(document).ready(function () { $('.js-affiliations-form').each((index, form) => { new AffiliationForm({ formId: form.id, institutionErrorSelector: '.comment-enter-institution', departmentErrorSelector: '.comment-enter-department', placeSelector: '.js-add-comment-place', stateSelector: '.js-add-comment-state', zipCodeSelector: '.js-add-comment-zipcode', countrySelector: '.js-add-comment-country', countryErrorSelector: '.comment-enter-country', }); }); }); $(document).ready(function () { var reportIds = { "50365": 0, "50366": 1, "50367": 0, }; $(".referee-response-container,.js-referee-report").each(function(index, el) { var reportId = $(el).attr("data-reportid"), reportCount = reportIds[reportId] || 0; $(el).find(".comments-count-container,.js-referee-report-views").html(reportCount); }); var uuidInput = $("#article_uuid"), oldUUId = uuidInput.val(), newUUId = "4574fcdd-9ea7-4170-82a8-3cda849ae100"; uuidInput.val(newUUId); $("a[href*='article_uuid=']").each(function(index, el) { var newHref = $(el).attr("href").replace(oldUUId, newUUId); $(el).attr("href", newHref); }); }); An innovative open access publishing platform offering rapid publication and open peer review, whilst supporting data deposition and sharing. Browse Gateways Collections How it Works Contact For Developers Cookie Notice Privacy Notice RSS Submit Your Research Follow us © 2012-2026 F1000 Research Ltd. ISSN 2046-1402 | Legal | Partner of Research4Life • CrossRef • ORCID • FAIRSharing R.templateTests.simpleTemplate = R.template(' $text $text $text $text $text '); R.templateTests.runTests(); var F1000platform = new F1000.Platform({ name: "f1000research", displayName: "F1000Research", hostName: "f1000research.com", id: "1", editorialEmail: "[email protected]", infoEmail: "[email protected]", usePmcStats: true }); $(function(){R.ui.dropdowns('.dropdown-for-authors, .dropdown-for-about, .dropdown-for-myresearch');}); // $(function(){R.ui.dropdowns('.dropdown-for-referees');}); $(document).ready(function () { if ($(".cookie-warning").is(":visible")) { $(".sticky").css("margin-bottom", "35px"); $(".devices").addClass("devices-and-cookie-warning"); } $(".cookie-warning .close-button").click(function (e) { $(".devices").removeClass("devices-and-cookie-warning"); $(".sticky").css("margin-bottom", "0"); }); $("#tweeter-feed .tweet-message").each(function (i, message) { var self = $(message); self.html(linkify(self.html())); }); $(".partner").on("mouseenter mouseleave", function() { $(this).find(".gray-scale, .colour").toggleClass("is-hidden"); }); }); Sign In Remember me Forgotten your password? Sign In Cancel Email or password not correct. Please try again Please wait... $(function(){ // Note: All the setup needs to run against a name attribute and *not* the id due the clonish // nature of facebox... $("a[id=googleSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("GOOGLE"); $("form[id=oAuthForm]").submit(); }); $("a[id=facebookSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("FACEBOOK"); $("form[id=oAuthForm]").submit(); }); $("a[id=orcidSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("ORCID"); $("form[id=oAuthForm]").submit(); }); }); If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password. The email address should be the one you originally registered with F1000. Email address not valid, please try again You registered with F1000 via Google, so we cannot reset your password. To sign in, please click here . If you still need help with your Google account password, please click here . You registered with F1000 via Facebook, so we cannot reset your password. To sign in, please click here . If you still need help with your Facebook account password, please click here . Code not correct, please try again Reset password Cancel Email us for further assistance. Server error, please try again. If your email address is registered with us, we will email you instructions to reset your password. If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance. Please wait... Register $(document).ready(function () { signIn.createSignInAsRow($("#sign-in-form-gfb-popup")); $(".target-field").each(function () { var uris = $(this).val().split("/"); if (uris.pop() === "login") { $(this).val(uris.toString().replace(",","/")); } }); });