Developing vision: Cadherin function in lens morphogenesis

这项应用的长期目标是了解晶状体早期发育的机制。我们将在理解晶状体诱导的遗传学和信号方面的最新进展的基础上，扩展到晶状体形态发生(定义为晶状体上皮形态变化，这是晶状体从胎盘发育到晶状体囊泡阶段的关键特征)的领域。我们正在进行的应用的具体目标是解决晶状体发育、信号和形态发生如何协调的问题。特别是，我们的初步证据表明，N-钙粘附素在晶状体形成中具有关键作用。N-钙粘附素是一种黏附分子，通过与肌动蛋白细胞骨架的C端连接，介导上皮细胞黏附和形态发生。N-钙粘附素也非常有趣，因为它具有激活或增强成纤维细胞生长因子信号的能力。我们将通过以下几个方面来研究N-钙粘附素的功能：目的1，确定N-钙粘附素的来源(S)对晶状体诱导至关重要；目的2，使用分子上位性分析将N-钙粘附素置于晶状体诱导的现有遗传途径中；目的3，通过评估N-钙粘附素在黏附、形态发生和成纤维细胞生长因子途径信号转导中的作用，确定为什么N-钙粘附素是晶状体诱导所必需的。研究N-钙粘附素在晶状体诱导中的作用是一个有趣的发育问题，显然，了解晶状体发育的基本机制可以为晶状体疾病的治疗提供未来的方向。然而，此外，最近有研究表明N-钙粘素可以促进肿瘤细胞的转移行为。从这个角度来看，我们的研究也将增强我们为癌症治疗计划治疗的能力。

The long-term goal of this application is an understanding of the mechanisms of early lens development. We will build on our recent progress in understanding the genetics and signaling of lens induction by extending into the area of lens morphogenesis (defined as the epithelial shape changes that are critical features of lens development from the stage of the lens placode to the lens vesicle). Our specific aims for the ongoing application are designed to address the question of how lens development signaling and morphogenesis are coordinated. In particular, our preliminary evidence has shown that N-cadherin has a critical function in lens formation. N-cadherin is an adhesion molecule that mediates epithelial adhesion and morphogenesis through a C-terminal connection to the actin cytoskeleton. N-cadherin is also very interesting because it has the ability to activate or enhance FGF signaling. We will investigate N-cadherin function by: Aim 1, determining which source(s) of N-cadherin, presumptive lens ectoderm and/or presumptive retina is critical for lens induction, Aim 2, using molecular epistasis analysis to place N-cadherin within the existing genetic pathway for lens induction, Aim 3, determining why N-cadherin is required for lens induction by assessing its role in adhesion, morphogenesis and FGF pathway signaling. Investigation of N-cadherin function in lens induction is an interesting developmental problem, and clearly, an understanding of the basic mechanisms of lens development can provide an indication of future directions for therapeutic resolution of lens disease. However, in addition, it has recently been shown that N-cadherin can contribute to the metastatic behavior of tumor cells. From this point of view, our studies will also enhance our ability to plan therapies for the treatment of cancer.