Fgfr3–Wnt signaling crosstalk is involved in maintaining cranial suture integrity.

Fgfr3–Wnt signaling crosstalk is involved in maintaining cranial suture integrity. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (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;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Fgfr3–Wnt signaling crosstalk is involved in maintaining cranial suture integrity. Rachel Pereur, Yvan Marc, Yuliya Lim, Alain Schmitt, Marilyne Malbouyres, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7093909/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Cranial suture formation is a dynamic process that requires precise cellular and molecular coordination to regulate bone growth and maintain suture homeostasis. The Fibroblast Growth Factor Receptor 3 (FGFR3) signaling pathway is among the major pathways disrupted in craniosynostosis; however, its precise role during cranial suture formation is still unknown. Using a relevant fgfr3 loss-of-function zebrafish model exhibiting abnormal suture morphology, we demonstrated for the first time that Fgfr3 plays a pleiotropic role in both the formation and maintenance of cranial sutures. Transmission electron microscopy and second harmonic generation imaging revealed that Fgfr3 is essential for the proper organization of the collagen network within the suture. Using specific transgenic reporter lines, we showed that Fgfr3 is crucial for regulating osteogenesis in this region. Specifically, Fgfr3 limits the number of osteoprogenitors at the osteogenic front and promotes osteoblast maturation at the suture edge. RNAscope analyses further revealed that loss of Fgfr3 led to significant upregulation of fgf18 expression and downregulation of the BMP antagonist grem1 within the suture. Finally, we investigated the Wnt/β-catenin signaling pathway and observed a marked overactivation in mutants compared to controls, notably evidenced by an upregulation of axin2. Pharmacological inhibition of this pathway during cranial suture development, using the β-catenin inhibitor XAV939, restored fgf18 expression, partially normalized grem1 levels, and led to a significant improvement in cranial suture morphology. In conclusion, these findings position Fgfr3 as a central regulator of cranial suture formation and homeostasis, acting through intricate cross-talk between the FGF, canonical Wnt, and possibly BMP signaling pathways. These data offer new insights into the biology of cranial suture and FGFR3-related craniosynostoses. Biological sciences/Physiology/Bone Health sciences/Diseases Full Text Additional Declarations There is no conflict of interest Supplementary Files Figuressupplement.pdf Supplemental Figures Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 23 Sep, 2025 Review # 2 received at journal 05 Sep, 2025 Reviewer # 2 agreed at journal 19 Aug, 2025 Review # 1 received at journal 29 Jul, 2025 Reviewer # 1 agreed at journal 28 Jul, 2025 Reviewers invited by journal 24 Jul, 2025 Submission checks completed at journal 14 Jul, 2025 Editor assigned by journal 10 Jul, 2025 First submitted to journal 10 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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The Fibroblast Growth Factor Receptor 3 (FGFR3) signaling pathway is among the major pathways disrupted in craniosynostosis; however, its precise role during cranial suture formation is still unknown.\r\nUsing a relevant fgfr3 loss-of-function zebrafish model exhibiting abnormal suture morphology, we demonstrated for the first time that Fgfr3 plays a pleiotropic role in both the formation and maintenance of cranial sutures. Transmission electron microscopy and second harmonic generation imaging revealed that Fgfr3 is essential for the proper organization of the collagen network within the suture. Using specific transgenic reporter lines, we showed that Fgfr3 is crucial for regulating osteogenesis in this region. Specifically, Fgfr3 limits the number of osteoprogenitors at the osteogenic front and promotes osteoblast maturation at the suture edge. RNAscope analyses further revealed that loss of Fgfr3 led to significant upregulation of fgf18 expression and downregulation of the BMP antagonist grem1 within the suture. Finally, we investigated the Wnt/β-catenin signaling pathway and observed a marked overactivation in mutants compared to controls, notably evidenced by an upregulation of axin2. Pharmacological inhibition of this pathway during cranial suture development, using the β-catenin inhibitor XAV939, restored fgf18 expression, partially normalized grem1 levels, and led to a significant improvement in cranial suture morphology. \r\nIn conclusion, these findings position Fgfr3 as a central regulator of cranial suture formation and homeostasis, acting through intricate cross-talk between the FGF, canonical Wnt, and possibly BMP signaling pathways. These data offer new insights into the biology of cranial suture and FGFR3-related craniosynostoses.","manuscriptTitle":"Fgfr3–Wnt signaling crosstalk is involved in maintaining cranial suture integrity.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-28 03:46:21","doi":"10.21203/rs.3.rs-7093909/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-09-23T09:35:36+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-09-05T05:37:07+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-08-19T15:43:46+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-07-29T17:49:51+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-07-28T13:33:30+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-07-25T03:47:42+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-14T07:14:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-10T14:12:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bone Research","date":"2025-07-10T14:12:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bone-research","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"boneres","sideBox":"Learn more about [Bone Research](http://www.nature.com/boneres/)","snPcode":"41413","submissionUrl":"https://mts-boneres.nature.com/cgi-bin/main.plex","title":"Bone Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e8e471e6-cb9c-47c6-84a3-1ea48e39f78a","owner":[],"postedDate":"July 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":52092881,"name":"Biological sciences/Physiology/Bone"},{"id":52092882,"name":"Health sciences/Diseases"}],"tags":[],"updatedAt":"2026-05-03T14:25:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-28 03:46:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7093909","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7093909","identity":"rs-7093909","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}