Notch Signaling and Lens Development

我们最近的研究表明Notch信号通路抑制晶状体纤维细胞分化。我们发现Herp2，一种转录抑制因子和Notch信号的效应因子，在靠近过渡区的晶状体上皮中表达。当Notch信号在晶状体中被特异性破坏时，Herp2表达缺失，晶状体上皮细胞过早分化为[1]。Notch信号如何阻断晶状体纤维细胞分化？我们提出Herp2抑制在晶状体纤维细胞形成中起关键作用的基因的表达。为了支持这一观点，我们发现p57Kip2是Herp2的转录靶点，p57Kip2是晶状体纤维细胞分化过程中细胞周期退出所需的Cdk抑制剂[2,3]。在这个修订后的提案中，我们将进一步了解Herp2如何在体外和体内抑制p57的表达。此外，我们最近的实验发现Prox1和α a结晶蛋白是Herp2的潜在靶点。由于这两个基因是已知的晶状体纤维细胞分化的调节因子，通过抑制它们的表达，Herp2（因此Notch信号）阻止了晶状体纤维细胞的分化。我们将通过体外和体内实验验证这一初步发现。

Our recent studies indicate that the Notch signaling pathway inhibits lens fiber cell differentiation. We found that Herp2, a transcriptional repressor and an effector of Notch signaling, was expressed in lens epithelium adjacent to the transition zone. When Notch signaling was disrupted specifically in the lens, Herp2 expression was lost and the lens epithelial cells prematurely differentiated [1]. How does Notch signaling block lens fiber cell differentiation? We propose that Herp2 suppresses the expression of genes that play critical roles in the formation of lens fiber cells. In support of that, we found p57Kip2, a Cdk inhibitor required for the cell cycle withdrawal during lens fiber cell differentiation [2, 3], was a transcriptional target of Herp2. In this revised proposal, we will further the understanding of how Herp2 suppresses p57 expression in vitro and in vivo. In addition, our recent experiments uncovered Prox1 and alphaA crystallin as potential targets of Herp2. Since these two genes are known regulators of lens fiber cell differentiation, by suppressing their expression, Herp2 (hence the Notch signaling) prevents the differentiation. We will validate this initial finding with in vitro and in vivo experiments.