BETA CATENIN SIGNALING DURING FEATHER TRACT DEVELOPMENT

器官和生物体生成的核心问题是将多能细胞以适当的位置和数量分配给不同的命运。 细胞间信号通路之间的相互作用，有助于这一过程似乎是常见的许多胚胎结构的产生。 羽场非常适合研究图案形成的早期步骤，因为能够参与这一过程的细胞的大而易接近的领域适合于在体内和体外操作。 羽芽是精确的图案结构，其形态发生由上皮和间充质信号中心的协调活动介导。 芽以精确的阵列相对于彼此定位，并且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阵列的规则性的中断。 本研究的长期目标是利用羽道来研究上皮间质相互作用产生的器官中信号通路之间的相互作用。 一些信号分子，包括骨形成蛋白、成纤维细胞生长因子和Notch及其配体的作用已部分阐明。 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。 该提案的重点是在管道发育期间定位该途径激活的机制。 将评估阻断该信号传导途径的影响，以基于功能实验的获得来完善观察结果。 Wnt家族的成员可以激活β-连环蛋白信号传导，因此将探索其在道形成过程中的表达和活性。 将在形态学和分子水平上评估逆转录病毒用于改变Wnt在卵内道中不同时间和位置的表达和活性的作用。 从体内工作中推断的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道发育的特定步骤的体外实验中进行测试。 空间或时间的差异，响应于外源性Wnts将被用来推断这个和其他信号传导途径之间的相互作用，和不同的TCF和Grgs在调制响应Wnts图案的道的作用将被调查。 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.