Vertebrate left-right asymmetry: the role of the homeobox gene Pitx2

左右不对称的产生可以分为三个阶段。一旦双侧对称性被破坏（I期），胚胎左侧和中线之间的信号传导事件，并返回到左侧板中胚层（I-LPM），导致TGD 3分子nodal的不对称表达（II期）。同源异型盒基因Pitx 2响应于结信号而被激活，并在不对称循环形态发生（阶段III）期间继续在心脏和肠道中表达。Pitx 2在偏侧性决定中的作用已经被导致器官位置倒置的错误表达实验所暗示。此外，Pitx 2在负反馈回路中起作用，以限制I-LPM中节点的活动。我们建议研究nodal和Pitx 2的调控网络。我们希望确定启动子元件，通过该启动子元件介导pitx 2诱导nodal，并研究导致nodal抑制的反馈环。这些实验应该揭示Pitx 2在侧化决策中的功能，并提供对LPM中信号通路调节的深入了解。此外，它们可以作为分析先天性心脏病的病因学的切入点，这些先天性心脏病是由有缺陷的心袢形成引起的。

The generation of left-right asymmetry can be divided into three stages. Once bilateral symmetry is broken (stage I), signaling events between the left side of the embryo and the midline, and back to the left lateral plate mesoderm (I-LPM) result in asymmetric expression of the TGDß molecule nodal (stage II). The homeobox gene Pitx2 gets activated in response to nodal signaling and continues to be expressed in the heart and gut during asymmetric looping morphogenesis (stage III). A role for Pitx2 in laterality determination has been implied by misexpression experiments which lead to inversion of organ situs. In addition Pitx2 acts in a negative feedback loop to restrict the activity of nodal in the I-LPM. We propose to study the regulatory network of nodal and Pitx2. We want to identify promoter elements through which Pitx2 induction by nodal is mediated and to investigate the feedback loop which results in repression of nodal. These experiments should reveal the function of Pitx2 in laterality decisions and provide insight into the regulation of signaling pathways in the LPM. In addition they may serve as an entry point to analyzing the etiology of congenital heart diseases which arise from defective heart loop formation.