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Regulation of Xenopus Embryonic Development by TGFbeta Superfamily Ligands and SM

TGFbeta 超家族配体和 SM 对非洲爪蟾胚胎发育的调节

基本信息

批准号：
8064547
负责人：
MALCOLM R. WHITMAN
金额：
$ 8.28万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-07 至 2012-08-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：我们的长期目标是了解TGF β超家族成员如何在发育过程中发挥广泛的细胞类型特异性作用。我们目前的重点是TGF？配体和它们的主要信号转导子Smads在两组发育事件中的作用：1）建立颅面骨骼和体壁肌肉组织的细胞群迁移的调节; 2）手术切除后尾部的正常生长和该结构的再生。细胞群在其终末分化之前在胚胎中长距离迁移是胚胎模式建立的关键组成部分。这些迁移涉及细胞行为和调控程序，这些程序可能在肿瘤转移过程中重现，因此了解它们的调控对肿瘤生物学和胚胎学非常重要。颅面骨骼主要由神经嵴细胞组成，神经嵴细胞从前神经板的边缘迁移到颅面区域，在那里它们分化成软骨和骨。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外侧体壁，在那里它们分化成肌肉。在每种情况下，初步工作暗示BMP信号作为细胞迁移和/或迁移细胞随后分化的调节剂。我们将使用我们实验室开发的一种新的条件性抑制剂来了解BMP如何调节这些过程。非洲爪蟾尾巴已被证明是一个强大的系统，用于研究复杂的再生事件的分子基础。我们已经确定了一个TGF β超家族配体，GDF 11，通过激活Smad 2控制正常尾部的生长。我们计划探索在尾部再生过程中GDF 11和Smad 2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控制细胞和组织迁移在正常发育过程中，在再生愈合后广泛的组织损伤，以及在病理过程中，如肿瘤转移，提供了一个新的途径，这些事件的治疗调节的基础。TGF的研究超家族配体提供了一种通用的方法和一套通用的分子工具，用于理解这些重要生理过程的调节。