The Circadian-Hippo-Telomerase Axis: A Novel Mechanistic Framework for Circadian Rhythm Disruption and Female Reproductive Homeostasis in Mice

The Circadian-Hippo-Telomerase Axis: A Novel Mechanistic Framework for Circadian Rhythm Disruption and Female Reproductive Homeostasis in Mice | 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 The Circadian-Hippo-Telomerase Axis: A Novel Mechanistic Framework for Circadian Rhythm Disruption and Female Reproductive Homeostasis in Mice Narmin Asadova, Elaza Aliyeva, Aylin Yaba This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9257776/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 3 You are reading this latest preprint version Abstract Circadian rhythms regulate reproductive physiology, but their disruption has been linked to infertility and endometrial pathologies. Here, we investigated how circadian rhythm disruption (12:12 h light/light cycle) affects the mouse ovary and uterus through the Hippo signaling pathway and telomerase reverse transcriptase (mTERT). Using histological, immunofluorescence, and qRT-PCR analyses, we evaluated PER2, YAP1, TEAD4, and mTERT expression. In ovaries, circadian disruption decreased PER2 and YAP1, while TEAD4 and mTERT levels increased. In contrast, uterine tissue exhibited epithelial thinning, glandular hyperplasia, and reduced myometrial thickness, accompanied by increased YAP1/TEAD4 expression and decreased mTERT. mRNA levels of circadian clock genes (BMAL1, CLOCK, PER2, and CRY1) remained largely unchanged, indicating post-transcriptional regulation. Collectively, our findings demonstrate tissue-specific adaptations of the ovary and uterus to circadian rhythm disruption, highlighting Hippo signaling as a potential mediator of reproductive dysfunction and mTERT as a divergent regulator in folliculogenesis versus endometrial remodeling. These findings have important implications for fertility preservation and suggest that targeting Hippo-mTERT signaling or restoring circadian alignment may represent promising therapeutic strategies for reproductive dysfunction associated with modern lifestyles, including shift work, jet lag, and artificial light exposure. Biological sciences/Cell biology Biological sciences/Developmental biology Health sciences/Endocrinology Biological sciences/Genetics Biological sciences/Molecular biology Biological sciences/Physiology Circadian rhythm ovary uterus Hippo signaling mTERT infertility Full Text Additional Declarations No competing interests reported. Supplementary Files Graphicalabstract.png Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 03 May, 2026 Submission checks completed at journal 03 May, 2026 First submitted to journal 03 May, 2026 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9257776","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":637196301,"identity":"7bfdda3c-6038-4312-bd3e-e6dbd97a064e","order_by":0,"name":"Narmin Asadova","email":"","orcid":"","institution":"Yeditepe University","correspondingAuthor":false,"prefix":"","firstName":"Narmin","middleName":"","lastName":"Asadova","suffix":""},{"id":637196302,"identity":"bae8433e-26cc-4b93-a8f9-8157f25b39e2","order_by":1,"name":"Elaza Aliyeva","email":"","orcid":"","institution":"Yeditepe University","correspondingAuthor":false,"prefix":"","firstName":"Elaza","middleName":"","lastName":"Aliyeva","suffix":""},{"id":637196303,"identity":"b3e51b90-7ab7-45f9-bde7-0220c8633048","order_by":2,"name":"Aylin Yaba","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFklEQVRIie3RsUrEMBjA8a9E4pIax5RA+wopLsoN9yo9HG450ak4HScHN/UBAudLuNxcCZxLyNzBwS7OBUFuOTA528Oh1tUh/yH9CP2R0gD4fP8ytCjbwT4xa3fxEAk6gjNH2JGQAdIORLg3/yZUTh7UHaiErvUna/LLOeXLEppcwZiXvYRVk4WSoFJpbjaRNIxFj9sskEYBOcv6j3GEgMpAhxserhgT1UygcGXJL1+WdCTR5J3vLRlXtw3aDxDREaEJ5oE7hc0ABQMk1bUlYpo+aXxxVRgWydeteC7MlBDdT+KXa/VB7kdJrFFd7fI5petl/bbLR/Fp0U/g3P0WcRhPvu/EriUM3SQtjyNqOuLz+Xy+n30BBV9al9RmvhIAAAAASUVORK5CYII=","orcid":"","institution":"Yeditepe University","correspondingAuthor":true,"prefix":"","firstName":"Aylin","middleName":"","lastName":"Yaba","suffix":""}],"badges":[],"createdAt":"2026-03-29 09:38:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9257776/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9257776/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109068114,"identity":"cfdb1b8c-4721-45ae-bb9b-8aff904dab79","added_by":"auto","created_at":"2026-05-12 10:03:44","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":911494,"visible":true,"origin":"","legend":"","description":"","filename":"Asadovaetal.2026.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9257776/v1_covered_0cb4481a-e0c1-4c12-8538-012c7433c864.pdf"},{"id":109020794,"identity":"41dc1216-6a85-49f9-94ac-7b9a7207383e","added_by":"auto","created_at":"2026-05-11 19:06:08","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":9687250,"visible":true,"origin":"","legend":"","description":"","filename":"Graphicalabstract.png","url":"https://assets-eu.researchsquare.com/files/rs-9257776/v1/e0b58578cc871a206f4771d2.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Circadian-Hippo-Telomerase Axis: A Novel Mechanistic Framework for Circadian Rhythm Disruption and Female Reproductive Homeostasis in Mice","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-biological-physics-and-mechanics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [npj Biological Physics and Mechanics](https://www.nature.com/npjbiolphysmech)","snPcode":"44341","submissionUrl":"https://submission.springernature.com/new-submission/44341/3","title":"npj Biological Physics and Mechanics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Circadian rhythm, ovary, uterus, Hippo signaling, mTERT, infertility","lastPublishedDoi":"10.21203/rs.3.rs-9257776/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9257776/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Circadian rhythms regulate reproductive physiology, but their disruption has been linked to infertility and endometrial pathologies. Here, we investigated how circadian rhythm disruption (12:12 h light/light cycle) affects the mouse ovary and uterus through the Hippo signaling pathway and telomerase reverse transcriptase (mTERT). Using histological, immunofluorescence, and qRT-PCR analyses, we evaluated PER2, YAP1, TEAD4, and mTERT expression. In ovaries, circadian disruption decreased PER2 and YAP1, while TEAD4 and mTERT levels increased. In contrast, uterine tissue exhibited epithelial thinning, glandular hyperplasia, and reduced myometrial thickness, accompanied by increased YAP1/TEAD4 expression and decreased mTERT. mRNA levels of circadian clock genes (BMAL1, CLOCK, PER2, and CRY1) remained largely unchanged, indicating post-transcriptional regulation. Collectively, our findings demonstrate tissue-specific adaptations of the ovary and uterus to circadian rhythm disruption, highlighting Hippo signaling as a potential mediator of reproductive dysfunction and mTERT as a divergent regulator in folliculogenesis versus endometrial remodeling. These findings have important implications for fertility preservation and suggest that targeting Hippo-mTERT signaling or restoring circadian alignment may represent promising therapeutic strategies for reproductive dysfunction associated with modern lifestyles, including shift work, jet lag, and artificial light exposure.","manuscriptTitle":"The Circadian-Hippo-Telomerase Axis: A Novel Mechanistic Framework for Circadian Rhythm Disruption and Female Reproductive Homeostasis in Mice","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-11 19:06:00","doi":"10.21203/rs.3.rs-9257776/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-05-04T00:04:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-03T11:37:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Biological Physics and Mechanics","date":"2026-05-03T11:31:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-biological-physics-and-mechanics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [npj Biological Physics and Mechanics](https://www.nature.com/npjbiolphysmech)","snPcode":"44341","submissionUrl":"https://submission.springernature.com/new-submission/44341/3","title":"npj Biological Physics and Mechanics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1da2f728-d41d-45b5-b551-700bdd3117c3","owner":[],"postedDate":"May 11th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewersInvited","content":"10","date":"2026-05-04T00:04:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-03T11:37:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Biological Physics and Mechanics","date":"2026-05-03T11:31:53+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":67824991,"name":"Biological sciences/Cell biology"},{"id":67824992,"name":"Biological sciences/Developmental biology"},{"id":67824993,"name":"Health sciences/Endocrinology"},{"id":67824994,"name":"Biological sciences/Genetics"},{"id":67824995,"name":"Biological sciences/Molecular biology"},{"id":67824996,"name":"Biological sciences/Physiology"}],"tags":[],"updatedAt":"2026-05-11T19:06:00+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-11 19:06:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9257776","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9257776","identity":"rs-9257776","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}