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

左右不对称的产生可分为三个阶段。一旦双侧对称性被打破（阶段I），胚胎左侧和中线之间的信号事件，以及回到左侧外侧板中胚层（I- lpm）导致TGDß分子节点的不对称表达（阶段II）。同源盒基因Pitx2在响应节点信号时被激活，并在不对称环路形态发生期间继续在心脏和肠道中表达（III期）。错误表达导致器官位置倒置的实验暗示了Pitx2在侧位决定中的作用。此外，Pitx2在I-LPM中起到负反馈回路的作用，限制了节点的活动。我们建议研究节点和Pitx2的调控网络。我们想确定启动子元件，通过其介导Pitx2诱导的节点和研究反馈回路，导致抑制节点。这些实验将揭示Pitx2在侧性决定中的功能，并为LPM中信号通路的调控提供见解。此外，它们可以作为一个切入点来分析先天性心脏病的病因，这些先天性心脏病是由有缺陷的心环形成引起的。

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.