Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States.
Invest Ophthalmol Vis Sci. 2020 Oct 1;61(12):21. doi: 10.1167/iovs.61.12.21.
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).
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.
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.
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.
yap1 编码一个进化上保守的转录共激活因子，作为 Hippo 信号通路的下游效应因子，该通路控制组织大小和细胞生长。yap1 有助于晶状体上皮细胞的发育。然而，yap1 杂合缺失对晶状体上皮细胞的影响及其在白内障形成中的作用尚未报道。本研究旨在研究 yap1 在晶状体上皮细胞 (LEC) 中的功能及其调控机制。
通过视觉观察、组织学和生化方法研究 yap1 杂合突变小鼠的晶状体表型。原代 LEC 培养物用于研究调节分子机制。
小鼠 yap1 杂合失活导致成年期白内障，LEC 表型异常。尽管眼部早期发育正常，包括晶状体，但大多数 yap1 杂合子在 6 个月大之前就会患上白内障。白内障前，晶状体上皮出现多种形态缺陷，包括细胞密度降低和细胞连接异常。低 LEC 密度与 LEC 增殖减少相一致。此外，yap1+/-LEC 中 yap1 靶基因 Crim1 的表达减少，而过表达 Crim1 可恢复 yap1+/-LEC 的体外增殖。
yap1 基因的纯合性对于维持 LEC 持续增殖和维持正常大小的晶状体所必需的 Crim1 表达至关重要。yap1 杂合缺失导致白内障。
