GENETIC REGULATORY NETWORK IN CRANIOFACIAL DEVELOPMENT

描述(由申请人提供)：这项建议的主要目标是研究哺乳动物颅面发育的基本机制。颅面的形态发生受表面与神经外胚层、内胚层、旁轴中胚层和颅神经脊之间的复杂相互作用的调节。这一过程高度依赖于迁徙的脑神经脊细胞的构型信息。大多数颅面畸形是由颅神经脊细胞的缺陷引起的，这些缺陷导致了包括颅骨在内的各种面部组织和结构。颅骨融合症是人类最常见的先天性颅面畸形之一，每2,500名婴儿中就有1人受到影响。颅缝融合的患者表现为颅骨异常，这是由颅缝和颅顶发育缺陷引起的。虽然遗传连锁分析已经提供了一些关于颅缝融合相关综合征的分子基础的信息，但对缝合和头骨发育的生物学知之甚少。在这项建议中，我们将研究基因改造小鼠的头盖骨形态发生和颅突闭合的遗传调控网络。我们已经培育出几个特别适合这些研究的小鼠品系。Axin2的突变严重影响了起源于神经脊的颅骨组织和结构的形成。在突变体中出现了类似于人类颅缝融合的表型缺陷。由于Axin2能够通过调节细胞内β-连环蛋白的水平来负向调节Wnt通路，我们认为Wnt-Axin信号网络在颅骨形态发生中起重要作用。我们将阐明由该信号网络介导的缝合发育的机制。这些研究有望为头面部发育和人类疾病的分子机制提供新的见解。

DESCRIPTION (provided by applicant): The primary objective of this proposal is to investigate the fundamental mechanisms that regulate mammalian craniofacial development. Craniofacial morphogenesis is regulated by complex interactions between the surface and neural ectoderms, endoderm, paraxial mesoderm and cranial neural crest. This process is highly dependent on the patterning information of emigrant cranial neural crest cells. The majority of craniofacial abnormalities are caused by defects in cranial neural crest cells that give rise to a variety of facial tissues and structures, including the cranial skull. Craniosynostosis affects 1 in ~2,500 infants and is 1 of the most common human congenital craniofacial deformities. Patients with craniosynostosis exhibit abnormal calvaria that are caused by defects in development of cranial suture and skull vault. Although genetic linkage analyses have provided some information on the molecular basis of craniosynostosis-related syndromes, very little is known about the biology of suture and skull development. In this proposal, we will study the genetic regulatory network that mediates calvarial morphogenesis and craniosynostosis in genetically modified mice. We have developed several mouse strains uniquely suited for these studies. Mutation of Axin2 severely affects formation of calvarial tissues and structures that are neural crest in origin. Phenotypic defects resembling craniosynostosis in humans developed in the mutants. Because of the abilities of Axin2 to negatively regulate the Wnt pathway by modulating the cellular levels of beta-catenin, we propose that the Wnt-Axin signaling network plays an important role in calvarial morphogenesis. We will elucidate the mechanism underlying suture development mediated by this signaling network. These studies promise new insights into the molecular mechanism of craniofacial development and human diseases.