GENETIC REGULATORY NETWORK IN CRANIOFACIAL DEVELOPMENT

描述（由申请人提供）：本提案的主要目的是研究调节哺乳动物颅面发育的基本机制。颅面形态发生受颅面表面与神经外胚层、内胚层、近轴中胚层和颅神经嵴之间复杂的相互作用调控。这一过程高度依赖于迁移的颅神经嵴细胞的模式信息。颅面畸形大多数是由颅神经嵴细胞缺陷引起的，颅神经嵴细胞缺陷导致各种面部组织和结构，包括颅颅骨。颅缝闭合症是人类最常见的先天性颅面畸形之一。颅缝闭合症患者表现为颅骨畸形，这是由颅骨缝线和颅骨穹窿发育缺陷引起的。虽然遗传连锁分析已经提供了一些关于颅缝愈合相关综合征的分子基础的信息，但对缝合和颅骨发育的生物学知之甚少。在本研究中，我们将研究转基因小鼠颅骨形态发生和颅缝闭合的基因调控网络。我们已经开发了几种适合这些研究的小鼠品系。Axin2突变严重影响以神经嵴为起源的头颅组织和结构的形成。在突变体中出现了类似于人类颅缝闭合的表型缺陷。由于Axin2能够通过调节β -连环蛋白的细胞水平负向调节Wnt通路，我们提出Wnt- axin信号网络在颅骨形态发生中起重要作用。我们将阐明该信号网络介导的缝线发育机制。这些研究为颅面发育和人类疾病的分子机制提供了新的见解。

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.