Notch Signaling and Lens Development

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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.