Regulation of Cell Signaling and Branching morphogenesis

分支形态发生是指上皮管的生长和分支，是血管系统、神经系统、肾脏、肺、胰腺、乳腺和唾液腺形成的基础。在分支过程中，上皮细胞的形态发生群形成分支，这些分支具有确定的分支模式、长度、直径、形状和间距，并经历大量的细胞活动。细胞是如何通过单一受体调节多种细胞活动的还不是很清楚。Ret受体酪氨酸激酶被其配体胶质细胞系衍生神经营养因子(GDNF)激活，导致肾脏发生多种细胞事件，是回答这一问题的一个有吸引力的模型。GDNF/Ret信号是如何调控的，以及它是如何改变上皮细胞的行为以经历许多不同的细胞过程尚不清楚。人们怀疑不同的信号通路的激活可能决定了生物产量。我们和其他人已经证明了？连环蛋白在许多器官系统的分支形态发生中是必不可少的。在细胞中，？连环蛋白通过与附着的连接结合而参与细胞黏附，或存在于细胞质/核成分中，转导Wnt信号。最近的研究表明，在多发性内分泌肿瘤中存在一种新的Ret激酶/？-catenin信号通路，来自我的实验室的数据有力地支持了这一新通路的重要作用。为了解决这种可能性，我建议：(1)通过确定是否对GDNF表达(以及其他已知的调节GDNF表达的基因)有直接影响，来检查？-catenin是否作用于Ret信号的上游；(2)询问？-catenin是否被激活以响应GDNF/Ret信号，并调节不同的基因和生物功能。这些发现可以应用于所有发育、成熟和疾病的器官系统，因为这里确定的信号通路和基因可能是基本过程。此外，GDNF/Ret信号对泌尿和神经系统的发育和维持是必不可少的。发现一个新的Ret/？-catenin信号通路可以为神经、肾脏和生殖系统的修复提供新的分子途径。

Branching morphogenesis, defined as the growth and branching of epithelial tubes, is fundamental to the formation of the vascular system, nervous system, kidney, lung, pancreas, mammary and salivary glands. During branching morphogenesis groups of epithelial cells form branches that have defined branch patterns, length, diameter, shape and spacing and undergo numerous cellular activities. How cells regulate multiple cellular events through a single receptor is not well understood. The activation of the Ret receptor tyrosine kinase by its ligand Glial cell-line derived neurotrophic factor (Gdnf) leads to multiple cellular events in the kidney and represents and attractive model to answer this question. How Gdnf/Ret signaling is regulated and how it alters the behavior of epithelial cells to undergo the many distinct cellular processes is not clear. It is suspected activation of distinct signaling pathways may determine the biological output. We and others have shown that ß-catenin is essential for branching morphogenesis in numerous organ systems. In the cell ß-catenin is involved in cell adhesion by binding to adherens junctions or is in a cytoplasmic/nuclear component that acts to transduce Wnt signals. Recent studies have demonstrated a novel Ret kinase/ß-catenin signaling pathway in multiple endocrine neoplasia's and data from my lab strongly supports an essential role for this novel pathway. To address this possibility I propose, to (1) examine if ß-catenin acts upstream of Ret signaling by determining if it has a direct effect on Gdnf expression (and other genes known to regulate Gdnf expression) and (2) to ask whether ß-catenin is activated in response to Gdnf/Ret signaling and regulates distinct genes and biological functions. These findings could be applied to all developing, mature, and diseased organ systems as the signaling pathway and genes identified here are likely fundamental processes. Further Gdnf/Ret signaling is essential for the development and maintenance of the urogential and nervous systems. Identifying a novel Ret/ß-catenin signaling pathway could provide novel molecular approaches for repair in the nervous, kidney and reproductive systems.