Regulation of Xenopus Embryonic Development by TGFbeta Superfamily Ligands and SM

描述(由申请人提供)：我们的长期目标是了解转化生长因子超家族的成员在发育过程中如何发挥广泛的细胞类型特异性作用。我们目前关注的是转化生长因子配体及其主要信号转导因子Smads在两组发育事件中的作用：1)建立颅面骨骼和体壁肌肉结构的细胞群迁移的调节；2)尾巴的正常生长和手术摘除后这种结构的再生。在胚胎的末端分化之前，细胞群体在胚胎中的远距离迁移是建立胚胎模式的关键组成部分。这些迁移涉及可能在肿瘤转移过程中重现的细胞行为和调控程序，使了解它们的调控对肿瘤生物学和胚胎学都很重要。颅面骨骼主要由神经脊细胞组成，这些细胞从前神经板的边缘迁移到颅面区域，在那里它们分化为软骨和骨。体壁的肌肉由肌肉前体细胞组成，这些细胞从体节迁移到腹侧体壁，在那里它们分化成肌肉。在每种情况下，初步工作都暗示BMP信号是细胞迁移和/或随后的迁移细胞分化的调节因素。我们将使用我们实验室开发的一种新的条件抑制物来了解BMP如何调节这些过程。非洲爪哇尾巴已被证明是研究复杂再生事件的分子基础的一个强大系统。我们已经确定了一个转化生长因子超家族配体GDF11，它通过激活Smad2来控制正常尾巴的生长。我们计划探索在尾巴再生过程中GDF11和Smad2的激活如何与其他信号通路相互作用，以建立再生程序。了解细胞外因子如何在正常发育期间、在广泛组织损伤后的再生愈合期间以及在肿瘤转移等病理过程中控制细胞和组织的迁移，为这些事件的治疗调控提供了新的途径。对转化生长因子超家族配体的研究提供了一种共同的方法和一套共同的分子工具，用来理解这些重要生理过程的调节。

DESCRIPTION (provided by applicant): Our long term goal is to understand how members of the TGF¿ superfamily act to exert a wide range of cell- type specific actions during development. Our current focus is on the role of TGF¿ ligands and their primary signal transducers, the Smads, in two sets of developmental events: 1) the regulation of migration of cell populations that establish the craniofacial skeleton and the body wall musculature; 2) the normal growth of the tail and the regeneration of this structure following surgical extirpation. Migration of cell populations over extended distances in the embryo prior to their terminal differentiation is a critical component of the establishment of embryonic pattern. These migrations involve cell behaviors and regulatory programs which may be recapitulated during tumor metastasis, making an understanding of their regulation important for tumor biology as well as embryology. The craniofacial skeleton is made up primarily of neural crest cells that migrate from the edge of the anterior neural plate into the craniofacial region, where they differentiate into cartilage and bone. The muscle of the body wall is made up of muscle precursor cells that migrate from the somites to the ventro-lateral body wall, where they differentiate into muscle. In each case, preliminary work implicates BMP signals as regulators of the cell migration and/or the subsequent differentiation of the migratory cell. We will use a novel conditional inhibitor developed in our lab to understand how BMPs regulate these processes. The Xenopus tail has been shown to be a powerful system for studying the molecular basis of complex regenerative events. We have identified a TGF¿ superfamily ligand, GDF11, that controls outgrowth of the normal tail through the activation of Smad2. We plan to explore how GDF11 and Smad2 activation during tail regeneration interacts with other signaling pathways to establish the regenerative program. Understanding how extracellular factors control cell and tissue migration during normal development, during regenerative healing following extensive tissue damage, and during pathological processes such as tumor metastasis, provides a basis for new paths to therapeutic regulation of these events. The study of TGF¿ superfamily ligands provides a common approach, and a common set of molecular tools, with which to understand the regulation of these important physiological processes.