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

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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.