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

这项研究的长期目标是了解哺乳动物胚胎中左/右（L/R）体轴决定的复杂遗传控制。L/R轴的规范建立了协调内脏发育的发育级联，并且对于器官系统和脉管系统的正确放置和对齐至关重要。有缺陷的L/R模式可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Tbx 6的作用。T先前已显示影响小鼠的偏侧性，尽管表型尚未完全探索。Tbx 6以前没有涉及偏侧性确定，但我们的初步研究和发表的工作揭示了突变体中的异位，表明该基因的重要作用，并显示了对Notch信号传导和节点内纤毛的影响。我们将研究这些基因，以确定缺陷的性质和机制。了解这些基因如何影响这一基本的发育过程将有助于了解L/R体轴决定的遗传和形态景观。 具体目标1。确定小鼠中与短尾畸形（T）突变相关的偏侧性缺陷的性质和机制，并将T和Tbx 6置于影响L/R决定的基因的遗传层次中。 具体目标2。在L/R轴测定时，检查Tbx 6和T突变胚胎中结和结纤毛的结构和功能。 具体目标3。确定淋巴结细胞相对于其先前Tbx 6表达的谱系。

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.