Epithelial Signaling of Mammalian Facial Topology

描述(申请人提供)：由基因改变和/或环境侮辱引起的颅面畸形是人类出生缺陷的最常见形式之一。在复杂的颅面结构形成过程中，精细的上皮-间充质和上皮-上皮相互作用对于面部隆起/肿胀的生长、图案化和融合至关重要。因此，了解这些相互作用的潜在分子机制对于理解面部形态发生和发病机制至关重要。这项研究的总体目标是确定调节面部形态发生的上皮信号，并最终建立颅面畸形治疗的分子靶点。与形成大多数面部骨骼结构的脑神经脊间充质细胞相比，人们对上皮性细胞在颅面形态发生中的作用知之甚少。我们的初步研究表明，对Wnt/β-catenin信号通路的上皮特异性操作会导致严重的面部畸形，包括颌骨畸形和唇腭裂(CL/P)。基于这些发现，我们假设上皮性Wnt/β-catenin信号通路是哺乳动物面部拓扑的关键诱导者。我们提出了两个互补的具体目标来检验这一假设。第一，揭示上皮性连环蛋白在颌骨形成过程中控制间充质细胞命运的机制；第二，阐明哺乳动物中面部形态发生的上皮特异性信号转导机制。

DESCRIPTION (provided by applicant): Craniofacial malformations resulting from genetic alterations and/or environmental insults are among the most common forms of human birth defects. Exquisite epithelial-mesenchymal and epithelial- epithelial interactions are critical for growth, patterning, and fusing of the facial prominences/swellings during formation of complex craniofacial structures. Therefore, understanding the underlying molecular mechanisms of these interactions is of paramount importance in understanding facial morphogenesis and pathogenesis. The overall goal of the proposed studies is to identify epithelial signals that regulate facial morphogenesis and ultimately to establish molecular targets of therapeutics for craniofacial anomalies. In contrast to the cranial neural crest-derived mesenchymal cells, which form most facial skeletal structures, relatively little is known about the epithelial contributions to craniofacial morphogenesis. Our preliminary studies demonstrate that epithelial-specific manipulations of the Wnt/¿ -catenin signaling pathway result in severe facial malformations, including jaw dysmorphism and the cleft lip and/or palate (CL/P). Based on these findings, we hypothesize that the epithelial Wnt/¿ -catenin signal pathway is the critical inducer of mammalian facial topology. We propose two complementary specific aims to test the hypothesis. First, to uncover the mechanisms by which epithelial ¿-catenin controls mesenchymal cell fate during jaw formation; second, to elucidate the epithelial-specific signaling mechanisms of mammalian middle face morphogenesis.