Developing vision: Cadherin function in lens morphogenesis

本申请的长期目标是了解早期透镜发育的机制。我们将建立在我们最近在理解透镜诱导的遗传学和信号传导方面的进展，通过扩展到透镜形态发生（定义为上皮形状变化，其是从透镜基板阶段到透镜囊泡阶段透镜发育的关键特征）领域。我们正在进行的申请的具体目标旨在解决透镜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-钙粘蛋白在透镜形成中具有关键作用。N-钙粘蛋白是一种粘附分子，通过C-末端连接到肌动蛋白细胞骨架介导上皮粘附和形态发生。N-钙粘蛋白也非常有趣，因为它具有激活或增强FGF信号传导的能力。我们将通过以下方式研究N-钙粘蛋白功能：目的1，确定N-钙粘蛋白的哪种来源、推定的透镜外胚层和/或推定的视网膜对于透镜诱导是关键的，目的2，使用分子上位性分析将N-钙粘蛋白置于透镜诱导的现有遗传途径内，目的3，通过评估N-钙粘蛋白在粘附中的作用来确定为什么N-钙粘蛋白对于透镜诱导是必需的，形态发生和FGF通路信号传导。 研究N-钙粘蛋白在透镜诱导中的功能是一个有趣的发展问题，很明显，了解透镜发育的基本机制可以为透镜疾病的治疗解决提供未来方向的指示。然而，此外，最近已经表明，N-钙粘蛋白可以有助于肿瘤细胞的转移行为。从这个角度来看，我们的研究也将提高我们计划治疗癌症的能力。

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.