ROLE OF TBX6 IN MESODERM PATTERING AND SOMITE FORMATION

TBX6 在中胚层模式和体节形成中的作用

• 批准号: 6520150
• 负责人: VIRGINIA E. PAPAIOANNOU
• 金额: $ 24.19万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520150
• 关键词: cell population study; developmental genetics; developmental neurobiology; embryogenic cleavage; gene mutation; genetically modified animals; laboratory mouse; mammalian embryology; mesoderm; myogenesis; neurogenesis; transcription factor

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.

描述（逐字附加研究者的摘要）：目标 这项研究旨在了解中胚层规范的遗传控制 原肠胚形成时并确定如何在关键时刻做出决策 之间的替代发展途径。假设是 1) 成员 Tbox 转录因子基因家族，特别是 Tbx6 是必不可少的 对于中胚层规范和分化，2）可能存在 Tbx6 亚家族的其他成员也参与其中。这些假设是 很大程度上基于我们在 Tbx6 等中产生的无效突变 其他物种的系统发育和突变研究。 Tbx6突变影响 中胚层的分化注定形成体节，并最终形成体节 大部分肌肉骨骼系统。在突变体中，发生了戏剧性的转变 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体节。 对于所有这些研究，小鼠将被用作模型系统，因为 它与人类相似，并且由于遗传的可用性 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，有助于理解 先天性异常以及肌肉和骨骼的慢性疾病。具体目标 1. 确定所有表达 Tbx6 的细胞的谱系以表征 充分了解 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 在中胚层规范中的作用机制 使用 Cremediad 转基因方法进行原肠胚形成，以实现 Tbx6 的错误表达。 具体目标 3. 产生一个新的 Tbx6 突变等位基因，编码截短的 仅具有 DNA 结合结构域且没有转录调控的蛋白质 领域。具体目标 4. 分离和表征其他成员 小鼠中的 Tbx6 亚家族，特别强调分离 其他物种中已知在中胚层发育中发挥作用的基因。