TGF-? SIGNALING DURING MOUSE SECONDARY PALATE ELEVATION AND FUSION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 腭裂是一种常见的出生缺陷，是由继发性腭裂发育畸形引起的。腭部的形成需要信号通路相互作用而不是孤立地发挥作用。然而，我们对腭部融合、生长和提升过程中的信号网络的了解仍然很差。拟议的研究将集中在腭部发育过程中主要信号通路之间的相互作用。转化生长因子β3是介导腭裂融合的重要信号分子，但其作用机制尚不清楚。我们发现，在融合过程中，Jag2的表达下调需要转化生长因子-β3，这表明转化生长因子-β和Notch通路在融合过程中发挥协同作用。Jag2、IRF6和IKA是防止病理性腭部与舌体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部粘连和融合方面的整合。我们将追求两个具体目标： 1)正常和病理性腭裂融合过程中转化生长因子β3、Notch1/Jag2之间的相互作用。我们将1)采用遗传学的方法来验证这一假说，即转化生长因子β3通过下调Jag2在MEE中的表达来介导腭裂融合；2)探讨Jag2下调在野生型腭裂融合中的功能意义。 Ii)研究上颌骨抬高过程中转化生长因子β信号转导及其与Wnt5a的相互作用。我们将1)研究Zfhx1a在腭部抬高过程中的下游靶基因，重点研究与细胞迁移相关的基因；2)通过产生转化生长因子β1，2双突变体来研究转化生长因子β1，2在腭部发育过程中的作用；3)研究转化生长因子βS对Wnt5a介导的非规范信号的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.