TGF-? SIGNALING DURING MOUSE SECONDARY PALATE ELEVATION AND FUSION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 腭裂是一种常见的出生缺陷，是由于腭裂继发发育畸形所致。腭的形成需要信号通路相互作用，而不是孤立的。然而，我们对腭融合、生长和升高过程中的信号网络的理解仍然很差。该研究将重点关注腭发育过程中主要信号通路之间的相互作用。TGF-β 3是介导腭融合的重要信号分子，但作用机制尚不清楚。我们发现TGF-β 3是在融合过程中下调Jag 2表达所必需的，表明TGF-β和Notch途径在融合过程中协同发挥作用。Jag 2、IRF 6和IKKa是防止致病性腭与舌和其他组织融合的关键调节因子，最近的研究揭示了这些因子在控制腭粘连和融合中的整合。我们将追求两个具体目标： I）正常和致病性腭融合期间TGF-β 3、Notch 1/Jag 2之间的相互作用。我们将1）采用遗传学方法来验证TGF-β 3通过下调Jag 2在腭部的表达来介导腭部融合的假设; 2)研究野生型腭融合过程中Jag 2下调的功能意义。 II）在腭提升期间TGF-β信号传导及其与Wnt 5a的相互作用的研究。我们将1）研究Zfhx 1a在腭部抬高过程中的下游靶基因，重点关注涉及细胞迁移的基因; 2）通过产生TGF-<$1，2双突变体来研究TGF-<$1，2在腭部抬高过程中的功能; 3）研究TGF-<$s对Wnt 5a介导的非经典信号传导的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cleft palate is a common birth defect caused by malformation in secondary palate development. Palate formation requires signaling pathways to function interactively rather than in isolation. However, our understanding of the signaling networks during palate fusion, growth and elevation remains poor. The proposed research will focus on the interactions among major signaling pathways during palate development. TGF-¿3 is an essential signaling molecule mediating palate fusion, but the mechanism of action is unknown. We found that TGF-¿3 is required for the down-regulation of Jag2 expression during fusion, suggesting TGF-¿ and Notch pathways function synergistically during fusion. Jag2, IRF6 and IKKa are key regulator factors in preventing pathogenic palate fusion with the tongue and other tissues, and recent studies have revealed the integration of these factors in controlling palate adhesion and fusion. We will pursue two specific aims: I) Interactions between TGF-¿3, Notch1/Jag2 during normal and pathogenic palate fusion. We will 1) take a genetic approach to test the hypothesis that TGF-¿3 mediates palate fusion by down-regulating Jag2 expression in the MEE; 2) investigate the functional significance of Jag2 down-regulation in MEE during wild type palate fusion. II) Investigation of TGF-¿ signaling and its interaction with Wnt5a during palate elevation. We will 1) investigate the downstream target genes of Zfhx1a during palate elevation focusing on the genes involving cell migration; 2) investigation of the function of TGF-¿1,2 during palate by generating TGF-¿1,2 double mutants; 3) examine the effects of TGF-¿s on Wnt5a mediated non-canonical signaling.