Yap1 is Essential for Lens Development and Exhibits Dose-Dependent Effects

Purpose: The Hippo-YAP pathway, which is crucial for regulating organ size, has been shown to play critical roles in lens development and homeostasis. However, Yap1's specific role in early lens morphogenesis is unclear. This study aims to investigate lens defects in Yap1 conditional knockout mice and explore the potential mechanisms. Methods: Lens-specific Yap1 deletion was induced using P0-3.9GFPCre in both Yap1fl/fl and Yap1fl/+ mice. Slit-lamp and brightfield imaging were used to observe the ocular phenotype. Lens histology was examined by H&E staining, while marker expression was analyzed using immunofluorescence and Western blot. Cellular proliferation and apoptosis were assessed via BrdU and TUNEL assays, respectively. RNA-seq was performed to profile the lens transcriptome. Results: Yap1 was consistently expressed throughout lens development. In contrast to previous reports, Yap1 deletion produced a continuous spectrum of lens defects, ranging from normal lenses to microphakia and, in the most severe cases, aphakia. The severity of these abnormalities exhibited a clear dose-dependent relationship with residual YAP1 protein levels. Notably, we identified lens–cornea adhesion as a previously unreported phenotype in Yap1-deficient mice, which may associate with reduced expression of the transcription factors FoxE3 and AP2α. The reduction in lens size was primarily attributable to impaired proliferation and a modest increase in apoptosis in lens epithelial cells. Conclusion: Our study identifies Yap1 as an essential regulator of early lens morphogenesis, acting through a finely tuned and highly dosage-sensitive regulatory mechanism.