ROLE OF TBX6 IN MESODERM PATTERING AND SOMITE FORMATION

描述（从研究者摘要中逐字附上）：目的 本研究旨在了解中胚层特化的遗传控制 并确定在关键时刻如何做出决定 不同的发展途径之间的联系假设：（1）成员 Tbox转录因子基因家族的成员，特别是Tbx6， 中胚层的特化和分化，以及2）可能存在 Tbx6亚家族的其他成员也参与其中。这些假设是 这在很大程度上是基于我们在Tbx6中产生的无效突变， 其他物种的系统发育和突变研究。Tbx6突变影响 中胚层的分化决定了体节的形成， 肌肉骨骼系统的大部分。在突变体中， 后中胚层向神经通路的分化途径 导致胚胎具有三个平行的神经管并且没有后部体节。 对于所有这些研究，小鼠将用作模型系统，因为 它与人类的相似之处， 资源了解控制发展的因素， 肌肉骨骼系统具有重要的健康相关性， 肌肉和骨骼的先天性异常和慢性疾病。具体目标1。 确定所有Tbx 6表达细胞的谱系，以表征 完整的Tbx6无效突变的表型结果，并检查 Tbx6无效细胞的发育潜力。具体目标2.探索 Tbx6在中胚层特化过程中的作用机制 使用Cre介导的转基因方法对Tbx6的错误表达进行原肠胚形成。 具体目标3。为了产生新的Tbx6突变等位基因，其编码截短的 一种只有DNA结合结构域而没有转录调控结构域的蛋白质 域具体目标4。要分离和表征 Tbx6亚家族在小鼠中的表达，特别强调分离Tbx6亚家族的直系同源物。 其他物种中已知的在中胚层发育中起作用的基因。

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.