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相互作用的调控。这一过程高度依赖于迁移的颅神经嵴细胞的图案信息。大多数颅面畸形是由颅神经嵴细胞的缺陷引起的，这些细胞产生各种面部组织和结构，包括颅骨。颅缝早闭影响约2，500名婴儿中的1名，是人类最常见的先天性颅面畸形之一。颅缝早闭患者表现为颅缝和颅骨穹窿发育缺陷引起的颅骨异常。虽然遗传连锁分析提供了一些信息的分子基础上的颅缝早闭相关综合征，很少有人知道的生物学缝和颅骨发育。在这个建议中，我们将研究介导转基因小鼠颅骨形态发生和颅缝早闭的遗传调控网络。我们已经开发了几种小鼠品系，特别适合这些研究。Axin 2的突变严重影响颅骨组织和结构的形成，这些组织和结构是神经嵴的起源。类似人类颅缝早闭症的表型缺陷在突变体中发展。由于Axin 2通过调节β-连环蛋白的细胞水平来负调节Wnt通路的能力，我们提出Wnt-Axin信号网络在颅骨形态发生中起重要作用。我们将阐明这个信号网络介导的缝合发展的机制。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.