BETA CATENIN SIGNALING DURING FEATHER TRACT DEVELOPMENT

器官和生物体产生的核心问题是多能细胞在适当位置和数量上的不同命运分配。促成这一过程的细胞间信号通路之间的相互作用似乎在许多胚胎结构的产生中是共同的。羽毛场非常适合研究模式形成的早期步骤，因为参与这一过程的大而可接近的细胞场可以在体内和体外进行操作。羽毛芽是一种精确的图案结构，其形态发生是由上皮和间充质信号中心协调活动介导的。芽彼此相对以精确的排列排列，组织芽的信号中心的形成或活动的任何扰动都很容易被检测为该排列规则的中断。该项目的长期目标是利用羽毛束来解剖由上皮间充质相互作用产生的器官中产生模式的信号通路之间的相互作用。一些信号分子的作用，包括bmp， FGFs和Notch及其配体，已经部分阐明。最近的研究表明，β -连环蛋白信号通路的激活是芽形成起始的关键步骤。这一建议的重点是该途径的激活在尿道发育过程中是局部的机制。阻断该信号通路的影响将被评估，以完善基于功能实验增益的观察结果。Wnt家族成员可以激活β -连环蛋白信号，因此我们将探讨它们在尿路形成过程中的表达和活性。我们将从形态学和分子水平上评估逆转录病毒在不同时间和不同位置改变wnt的表达和活性的影响。从体内工作推断出的β -连环蛋白途径和激活它的wnt的顺序作用将在一系列针对肠道发育特定步骤的体外实验中进行测试。对外源性wnt反应的空间或时间差异将用于推断这一信号通路与其他信号通路之间的相互作用，并将研究不同的tcf和Grgs在调节对wnt的反应性方面的作用。这将增强我们对许多器官形成的理解，并提出控制由β -连环蛋白信号通路活性失调引起的发育缺陷和癌症的策略。

A problem central to the generation of organs and organisms is the allocation of multipotent cells to different fates in appropriate positions and numbers. The interactions between intercellular signaling pathways which contribute to this process appear to be common to the generation of many embryonic structures. The feather field is well suited to study the early steps of pattern formation because the large and accessible fields of cells competent to participate in this process are amenable to manipulation both in vivo and in vitro. Feather buds are precisely patterned structures whose morphogenesis is mediated by co-ordinated activity of epithelial and mesenchymal signaling centers. Buds are positioned relative to each other in a precise array and any perturbation in the formation or activity of the signaling centers that organize the bud is readily detected as an interruption in the regularity of that array. The long term goal of this project is to employ the feather tract to dissect the interactions between signaling pathways that generate pattern in organs generated by epithelial mesenchymal interactions. The roles of several signaling molecules, including BMPs, FGFs and Notch and its ligands, have been partially elucidated. Recent work has demonstrated that activation of the beta-catenin signaling pathway is a crucial step in initiation of bud formation. This proposal focuses on the mechanisms by which activation of this pathway is localized during tract development. The effects of blocking this signaling pathway will be assessed to refine observations based on gain of function experiments. Members of the Wnt family can activate beta-catenin signaling, so their expression and activity during tract formation will be explored. The effects of retroviruses employed to alter the expression and activity of Wnts at different times and positions in the tract in ovo will be assessed at the morphological and molecular levels. The sequential roles of the beta-catenin pathway and the Wnts that activate it that are inferred from in vivo work will be tested in a series of in vitro experiments targeted to specific steps of tract development. Spatial or temporal differences in response to exogenous Wnts will be used to infer the interaction between this and other signaling pathways, and the roles of different TCFs and Grgs in modulating responsiveness to Wnts to pattern the tract will be investigated. This should enhance our understanding of the formation of many organs as well as suggest strategies to control the developmental defects and cancer that are caused by deregulated activity of the beta-catenin signaling pathway.