BETA CATENIN SIGNALING DURING FEATHER TRACT DEVELOPMENT

器官和生物体生成的一个核心问题是将多能细胞分配给不同命运的适当位置和数量。参与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常见的。羽毛场非常适合于研究图案形成的早期步骤，因为有能力参与这一过程的大而可及的细胞场在体内和体外都可以操纵。羽芽是精确图案化的结构，其形态发生是由上皮性和间叶性信号中心的协调活动所介导的。芽被相对于彼此定位在精确的阵列中，并且组织芽的信号中心的形成或活动中的任何扰动都容易被检测为该阵列的规律性的中断。该项目的长期目标是利用羽毛束来剖析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，包括BMPs、FGFs和Notch及其配体的作用已被部分阐明。最近的工作表明，激活β-连环蛋白信号通路是启动芽形成的关键步骤。这项建议的重点是激活该途径的机制，通过它定位在肠道发育过程中。阻断这一信号通路的效果将被评估，以基于功能实验的增益来完善观察。Wnt家族的成员可以激活β-连环蛋白信号，因此我们将探讨它们在神经束形成过程中的表达和活性。利用逆转录病毒在OVO的不同时间和位置改变WNTS的表达和活性的效果将在形态和分子水平上进行评估。从体内工作中推断出的β-连环蛋白途径和激活它的WNTS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WNTs的反应的空间或时间差异将被用来推断该信号通路与其他信号通路之间的相互作用，并且将研究不同的TCFs和GRG在调节对WNTs的反应以形成通路的过程中所起的作用。这将加强我们对许多器官形成的理解，并提出控制发育缺陷和癌症的策略，这些缺陷和癌症是由β-连环蛋白信号通路的失控活性引起的。

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.