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

点击翻译按钮获取中文摘要

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.