ROLE OF TBX6 IN MESODERM PATTERING AND SOMITE FORMATION

说明(逐字摘自调查员摘要)：目标 这项研究是为了了解中胚层的遗传控制规范 在原肠形成时，并确定如何在关键时刻做出决定 在不同的发育途径之间。假设是1)成员 在Tbox转录因子基因家族中，尤其是Tbx6是必不可少的 对于中胚层的规范和分化，以及2)可能有 Tbx6亚家族的其他成员也参与其中。这些假设是 在很大程度上基于我们在Tbx6和 其他物种的系统发育和突变研究。Tbx6突变会影响 中胚层分化形成体节，最终形成体节 肌肉骨骼系统的大部分。在变种人中有一个戏剧性的转变 后中胚层向神经通路分化的途径 导致胚胎有三个平行的神经管，没有后部体节。 在所有这些研究中，鼠标将被用作模型系统，因为 它与人类的相似性，因为基因的可获得性 资源。了解控制经济发展的因素 肌肉骨骼系统对了解人体健康有重要意义 肌肉和骨骼的先天畸形和慢性疾病。具体目标1. 确定所有表达Tbx6的细胞的谱系以确定其特征 完整的Tbx6零突变的表型结果，并检查 Tbx6缺失细胞的发育潜能。具体目标2.探索 Tbx6在中胚层发育过程中的作用机制 Tbx6基因错误表达的原肠形成 具体目的3.产生一个新的Tbx6突变等位基因，编码一个截短的 只有DNA结合域而没有转录调控的蛋白质 域。具体目标4.分离和鉴定该病毒的其他成员 小鼠中的Tbx6亚家族，特别强调分离 在其他物种中已知的基因在中胚层发育中发挥作用。

DESCRIPTION (appended verbatim from investigator's abstract): The objectives of this research are to understand the genetic control of mesoderm specification at gastrulation and to determine how decisions are made at critical junctures between alternative developmental pathways. The hypotheses are 1) that members of the Tbox transcription factor gene family in particular Tbx6 are essential for mesoderm specification and differentiation and 2) that there may be additional members of the Tbx6 subfamily also involved. These hypotheses are based in large part on the null mutation we have produced in Tbx6 and on phylogenetic and mutational studies in other species. The Tbx6 mutation affects the differentiation of mesoderm destined to form the somites and eventually the bulk of the musculoskeletal system. In mutants there is a dramatic switch in the differentiation pathway of posterior mesoderrn to a neural pathway resulting in embryos with three parallel neural tubes and no posterior somites. For all of these studies the mouse will be used as a model system because of its similarity to the human and because of the availability of genetic resources. Understanding the factors that control the development of the musculoskeletal system has important health relatedness for understanding congenital anomalies and chronic diseases of muscles and bone. Specific Aim 1. To determine the lineage of all Tbx6expressing cells in order to characterize fully the phenotypic results of a null mutation in Tbx6 and to examine the developmental potential of Tbx6 null cells. Specific Aim 2.To explore the mechanism of action of Tbx6 in the specification of mesoderm during gastrulation using a Cremediated transgenic approach for misexpression of Tbx6. Specific Aim 3. To produce a new Tbx6 mutant allele coding for a truncated protein with only the DNA binding domain and no transcriptional regulatory domain. Specific Aim 4. To isolate and characterize additional members of the Tbx6 subfamily in the mouse with special emphasis on isolating the orthologs of genes known in other species to play a role in mesoderm development.