T-box gene effects on left-right body axis determination

T-box基因对左右身体轴测定的影响

• 批准号: 7895071
• 负责人: VIRGINIA E. PAPAIOANNOU
• 金额: $ 37.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895071
• 关键词: Affect; Alleles; Biological Process; Blood Vessels; Boxing; Brachyury protein; Cardiac; Cell Lineage; Cilia; Complex; Congenital Heart Defects; Data; Defect; Development; Developmental Process; Embryo; Event; Gene Targeting; Genes; Genetic; Goals; Handedness; Health; Investigation; Lead; Left; Life Expectancy; Ligands; Mesoderm; Mus; Mutation; Nature; Nodal; Organ; Orthologous Gene; Pathway interactions; Pattern; Phenotype; Play; Process; Publishing; Research; Role; Signal Pathway; Signal Transduction; Situs Inversus; Spleen; Staging; Structure; Testing; Time; Transcription factor genes; Viscera; Work; body asymmetry; body system; mutant; notch protein; notochord; novel; transcription factor

The long-term goal of the proposed research is to understand the complex genetic control of determination of left/right (L/R) body axis in the mammalian embryo. Specification of the L/R axis sets up a developmental cascade that coordinates development of the viscera and is essential for the correct placement and alignment of organ systems and vasculature. Defective L/R patterning can lead to congenital cardiac malformations, vascular anomalies and other serious health issues. We will investigate the roles of two T-box transcription factor genes, Brachyury (T) and Tbx6. T has previously been shown to affect laterality in mice although the phenotype has not been fully explored. Tbx6 had not previously been implicated in laterality determination, but our preliminary studies and published work reveals heterotaxia in mutants, indicating an important role for this gene, and shows effects on Notch signaling and cilia within the node. We will investigate these genes to determine the nature and mechanism of the defects. Understanding how these genes impinge on this basic developmental process will add to understanding of the genetic and morphological landscape within w hich the L/R body axis is determined. Specific Aim 1. To determine the nature and mechanisms of the laterality defects associated with Brachyury (T) mutation in the mouse and place T and Tbx6 in the genetic hierarchy of genes affecting L/R determination. Specific Aim 2. To examine the structure and function of the node and nodal cilia in Tbx6 and T mutant embryos at the time of L/R axis determination. Specific Aim 3. To determine the lineage of cells of the node with respect to their prior expression of Tbx6.

这项研究的长期目标是了解哺乳动物胚胎中决定左/右(L/R)体轴的复杂基因控制。L/R轴的指定建立了一个发育级联，协调内脏的发育，对于器官系统和血管系统的正确放置和对齐至关重要。L/R图案缺陷会导致先天性心脏畸形、血管异常和其他严重的健康问题。我们将研究两个T-box转录因子基因brachyury(T)和Tbx6的作用。尽管T的表型还没有完全被探索，但之前已经证明T影响小鼠的偏侧性。Tbx6以前没有涉及到侧向性决定，但我们的初步研究和发表的工作揭示了突变体的异质性，表明该基因具有重要作用，并显示了对Notch信号和节内纤毛的影响。我们将对这些基因进行研究，以确定缺陷的性质和机制。了解这些基因是如何影响这一基本发育过程的，将有助于理解L/R体轴确定的遗传和形态格局。 具体目的1.确定与短臂(T)突变相关的小鼠偏侧缺陷的性质和机制，并将T和Tbx6置于影响L/R决定的基因的遗传层次中。 具体目的2.在L/R轴测定时，观察Tbx6和T突变胚胎的节状和节状纤毛的结构和功能。 具体目的3.确定结节细胞与其先前表达的Tbx6的谱系。

项目成果

Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells.

• DOI: 10.1038/nature09729
• 发表时间: 2011-02-17
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Takemoto, Tatsuya;Uchikawa, Masanori;Yoshida, Megumi;Bell, Donald M.;Lovell-Badge, Robin;Papaioannou, Virginia E.;Kondoh, Hisato
• 通讯作者: Kondoh, Hisato