{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T04:27:25Z","timestamp":1787632045905,"version":"build-2736575974"},"reference-count":143,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 HD098106 (YX)"],"award-info":[{"award-number":["R01 HD098106 (YX)"]}]},{"name":"NIH","award":["R21 ES033342 (YX)"],"award-info":[{"award-number":["R21 ES033342 (YX)"]}]},{"name":"NIH","award":["R21HD118374 (YX)"],"award-info":[{"award-number":["R21HD118374 (YX)"]}]},{"award":["R01 HD098106 (YX)"],"award-info":[{"award-number":["R01 HD098106 (YX)"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21 ES033342 (YX)"],"award-info":[{"award-number":["R21 ES033342 (YX)"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21HD118374 (YX)"],"award-info":[{"award-number":["R21HD118374 (YX)"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Developmental disorders often arise from complex interactions between genetic variation and environmental factors, yet the molecular mechanisms underlying gene-gene (G \u00d7 G) and gene-environment (G \u00d7 E) interactions remain poorly understood. Mouse embryonic eyelid closure provides a genetically tractable in vivo model for investigating these mechanisms. Eyelid closure requires coordinated epithelial migration and cytoskeletal remodeling orchestrated by interconnected signaling pathways. Among these pathways, MAP3K1 functions as a critical signaling hub that integrates inputs from S1PR-RHOA-ROCK and other upstream regulators to activate JNK and promote eyelid closure. Genetic studies show that multiple components within the GPCR-RHOA-ROCK-MAP3K1-JNK network cooperate to maintain developmental robustness. Reducing the activity of pathway components dose-dependently impairs eyelid closure and produces the characteristic eye-open-at-birth (EOB) phenotype. Environmental factors also converge on this network. Although exposure to dioxin does not impair eyelid closure in wild-type embryos, it induces EOB in embryos harboring otherwise phenotypically silent mutations in the MAP3K1 network, such as Map3k1+\/\u2212, Jnk1\u2212\/\u2212 and S1pr2\u2212\/\u2212. These findings identify the MAP3K1 pathway as a point of convergence of genetic and environmental signals and establish embryonic eyelid closure as a powerful model for elucidating molecular mechanisms underlying developmental robustness, susceptibility and resilience.<\/jats:p>","DOI":"10.3390\/cells15171508","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T08:03:41Z","timestamp":1787558621000},"page":"1508","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MAP3K1 Integrates Genetic and Environmental Signals in Eyelid Morphogenesis"],"prefix":"10.3390","volume":"15","author":[{"given":"Bo","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, 160 Panzeca Way, Cincinnati, OH 45267-0056, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winston","family":"Kao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0527, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9532-9527","authenticated-orcid":false,"given":"Ying","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, 160 Panzeca Way, Cincinnati, OH 45267-0056, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/gm28","article-title":"Gene-gene and gene-environment interactions: New insights into the prevention, detection and management of coronary artery disease","volume":"1","author":"Lanktree","year":"2009","journal-title":"Genome Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s13073-017-0506-1","article-title":"Challenges in understanding common disease","volume":"9","author":"Visscher","year":"2017","journal-title":"Genome Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Xintong, Z., Kexin, Z., Junwen, W., Ziyi, W., Na, L., and Hong, G. 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