Cell-cell communication in Xenopus development

描述（由申请人提供）：蛙爪蟾的早期胚胎为发现控制细胞信号传导和分化的分子机制提供了有利的系统。当一个胚胎被切成两半时，它可以自我调节，形成一个匀称的有机体。最近的实验已经阐明，自我调节是由一种新的细胞外生化途径介导的。BMP家族生长因子的信号传导被一种称为Chordin的背侧蛋白质拮抗。脊索蛋白被Tolloid家族的腹侧表达的锌金属蛋白酶降解。反过来，这种蛋白酶被腹侧分泌的卷曲相关蛋白（sFRP）抑制。在这里，我们打算通过探索三个广泛的问题来研究细胞-细胞信号传导：1）胚胎背极和腹极的细胞如何长距离相互通信？我们的假设是，类似的生化活性的分泌分子表达在胚胎的两极，但相反的转录控制下，提供了理解分化细胞自我调节的发育领域的关键。2)其他sFRPs是锌金属蛋白酶的抑制剂吗？要测试的假设是，卷曲结构域，这是存在于许多细胞外蛋白，可能提供一个模块，调节细胞外分子的蛋白水解，也许在Wnt生长因子的控制下。3)多种生长因子信号输入如何在细胞内整合？我们将测试BMP、Wnt和受体酪氨酸激酶信号通路是否会聚在转录因子Smadl的磷酸化状态上，从而调节其活性。研究这三个具体目标将有助于提供一个综合的观点，细胞如何相互沟通，不仅在胚胎中，而且在成人组织和人类胚胎干细胞中。待研究的信号通路中的基因涉及许多医学相关的过程，例如中枢神经系统诱导、细胞和组织分化、同卵双胞胎和连体双胞胎的形成、神经诱导、纤维化和结缔组织疾病以及癌症。

Description (provided by applicant): The early embryo of the frog Xenopus provides a favorable system for discovering the molecular mechanisms that control cell signaling and differentiation. When an embryo is cut in half, it can self-regulate to form a well-proportioned organism. Recent experiments have elucidated that self-regulation is mediated by a novel extracellular biochemical pathway. Signaling by the BMP family of growth factors is antagonized by a dorsal protein called Chordin. Chordin is degraded by a ventrally-expressed zinc metalloproteinase of the Tolloid family. In turn, this protease is inhibited by a ventrally secreted Frizzled-Related Protein (sFRP). Here we propose to investigate cell-cell signaling by exploring three broad questions: 1) How do cells in the dorsal and ventral poles of the embryo communicate with each other across long distances? Our hypothesis is that secreted molecules of similar biochemical activity expressed at opposite poles of the embryo, but under opposite transcriptional control, provide the key to understanding how developmental fields of differentiating cells self-regulate. 2) Are other sFRPs inhibitors of zinc metalloproteinases? The hypothesis to be tested is that Frizzled domains, which are present in many extracellular proteins, might provide a module that regulates the proteolysis of extracellular molecules, perhaps under the control of Wnt growth factors. 3) How are multiple growth factor signaling inputs integrated intracellularly? We will test whether the BMP, Wnt, and Receptor Tyrosine Kinase signaling pathways converge on the phosphorylation state of the transcription factor Smadl, regulating its activity. Investigating these three specific aims will help provide an integrated view of how cells communicate with each other, not only in embryos but also in adult tissues and in human embryonic stem cells. Genes in the signaling pathways to be studied are involved in many processes of medical relevance, such as central nervous system induction, cell and tissue differentiation, the formation of identical and conjoined twins, neural induction, fibrotic and connective tissue disease, and cancer.