MAP3K1 Integrates Genetic and Environmental Signals in Eyelid Morphogenesis
TL;DR
The MAP3K1 pathway is identified 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.
Abstract
Developmental disorders often arise from complex interactions between genetic variation and environmental factors, yet the molecular mechanisms underlying gene-gene (G × G) and gene-environment (G × 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+/−, Jnk1−/− and S1pr2−/−. 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.