Heterozygous Loss of Yap1 in Mice Causes Progressive Cataracts

Abstract

Purpose Yap1 encodes an evolutionarily conserved transcriptional coactivator and functions as a down-stream effector of the Hippo signaling pathway that controls tissue size and cell growth. Yap1 contributes to lens epithelial development. However, the effect of Yap1 haplodeficiency on the lens epithelium and its role in the development of cataracts has not been reported. The aim of the current study is to investigate Yap1 function and its regulatory mechanisms in lens epithelial cells (LECs). Methods Lens phenotypes were investigated in Yap1 heterozygous mutant mice by visual observation and histological and biochemical methods. Primary LEC cultures were used to study regulatory molecular mechanism. Results The heterozygous inactivation of Yap1 in mice caused cataracts during adulthood with defective LEC phenotypes. Despite a normal early development of the eye including the lens, the majority of Yap1 heterozygotes developed cataracts in the first six months of age. Cataract was preceded by multiple morphological defects in the lens epithelium, including decreased cell density and abnormal cell junctions. The low LEC density was coincident with reduced LEC proliferation. In addition, expression of the Yap1 target gene Crim1 was reduced in the Yap1 +/ − LEC, and overexpression of Crim1 restored Yap1 +/ − LEC cell proliferation in vitro. Conclusions Homozygosity of the Yap1 gene was critical for adequate Crim1 expression needed to maintain the constant proliferation of LEC and to maintain a normal - sized lens. Yap1 haplodeficiency leads to cataracts.

The Hippo signalling pathway and its implications in human health and diseases

“…293 In addition to retinal-related diseases, the heterozygous inactivation of YAP1, which decreases the expression of YAP1 protein in lens epithelia, results in cataracts with lens epithelial cell defects. 294 Moreover, NF2 deficiency in the lens epithelium in mice could lead to a cataract phenotype. 64 The Hippo pathway in cardiac diseases.…”

The Hippo signalling pathway and its impact on eye diseases

“…33 In addition, YAP is necessary to preserve the normal size of the lens. 34 The lens epithelium was significantly reduced in mice with conditionally deleted YAP. 33 Loss of YAP inhibits proliferation, promotes abnormal differentiation and senescence of LECs, and eventually leads to an abnormal lens structure and nuclear cataract formation.…”

“…22 Recent studies have demonstrated that, in mice, one allelic deletion of Yap1 dramatically lowered LEC cell density, disrupted local cell adhesion and caused cataracts. 34,35 Liu et al…”

“…It also maintains LEC shape by stabilizing junctional proteins and apical polarity complexes 33 . In addition, YAP is necessary to preserve the normal size of the lens 34 . The lens epithelium was significantly reduced in mice with conditionally deleted YAP 33 .…”

CCN–Hippo YAP signaling in vision and its role in neuronal, glial and vascular cell function and behavior

“…Gain or loss of YAP function modulates the expression of genes that regulate cell proliferation and survival (diap1, bantam, cyclin E, and E2F1), the Hippo pathway (Kibra, Crb, and Fj), and cell-cell interaction (E-Cadherin, Serrate, Wingless, and Vein) (Pan 2010). The role of YAP in the regulation of ocular tissue development and function has been extensively studied (Kastan et al 2022;Lu et al 2020). Indeed, YAP has been shown to be expressed in the RPE and the ciliary margin of the optic cup as well as corneal epithelial and lens epithelial cells, iris, and retina where it localized in the inner nuclear layer (Hamon et al 2019(Hamon et al , 2017.…”