Rab23 function in nodal signaling during left-right patterning in the mouse

描述(申请人提供)：脊椎动物的身体平面是在发育过程中沿着其左右轴形成图案的。这确保了器官在体内的位置不对称，并且心脏和肺等单个器官采用了不对称的结构。在我们的胚胎发育过程中，如果这个过程失败，会导致危及生命的疾病，如先天性心脏缺陷。左右模式在很大程度上是由胚胎左侧用于细胞间交流的Nodal信号通路的不对称活动控制的。在这里，我们研究了蛋白Rab23在胚胎结节信号中的作用。缺乏Rab23的小鼠胚胎由于未能激活左侧的Nodal信号而出现左右图案缺陷。我们将研究Rab23功能是细胞内对Nodal信号的反应所必需的，还是细胞产生作用于相邻细胞的功能信号所必需的。我们还将在胚胎和培养细胞中使用分子方法来测试Rab23控制信号GDF1的分泌或修改的假设，GDF1与Nodal一起作用以适当地激活细胞反应。 与公共卫生相关：人类胚胎发育过程中左右模式的缺陷通常会导致危及生命的疾病，如先天性心脏缺陷。这项提议研究了哺乳动物左-右模式背后的细胞和生化机制。

DESCRIPTION (provided by applicant): The vertebrate body plan is patterned along its left-right axis during development. This ensures that organs are positioned asymmetrically within the body, and that individual organs such as the heart and lungs, adopt an asymmetric structure. Failure of this process during our embryonic development, results in life-threatening disorders such as congenital heart defects. Left-right patterning is governed largely by the asymmetric activity of the Nodal signaling pathway, used for intercellular communication, on the left side of the embryo. Here, we investigate the role of the protein Rab23 in embryonic Nodal signaling. Mouse embryos lacking Rab23 exhibit left-right patterning defects as a result of their failure to activate Nodal signaling on the left side. We will investigate whether Rab23 function is required within cells for their response to Nodal signals or for cells to produce functional signals that act on their neighbors. We will also use molecular methods in the embryo, as well as cells in culture, to test the hypothesis that Rab23 controls the secretion or modification of the signal GDF1, which acts together with Nodal to properly activate cellular responses. PUBLIC HEALTH RELEVANCE: Defects in left-right patterning during human embryogenesis often lead to life-threatening conditions such as congenital heart defects. This proposal investigates the cellular and biochemical mechanisms that underlie left-right patterning in mammals.