GENETIC REGULATORY NETWORK IN CRANIOFACIAL DEVELOPMENT

颅面发育中的遗传调控网络

• 批准号: 7835696
• 负责人: Wei Hsu
• 金额: $ 34.03万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7835696
• 关键词: Affect; Biology; Bone Development; Calvaria; Cephalic; Complex; Craniofacial Abnormalities; Craniosynostosis; Data; Defect; Deformity; Development; Ectoderm; Embryonic Development; Emigrant; Endoderm; Exhibits; FGFR1 gene; Face; Feedback; Fibroblast Growth Factor; Gene Family; Genetic; Genetic Transcription; Human; Infant; Joint structure of suture of skull; Mediating; Mesenchyme; Mesoderm; Molecular; Morphogenesis; Mouse Strains; Mus; Mutation; Neural Crest; Neural Crest Cell; Osteoblasts; Paraxial Mesoderm; Pathway interactions; Patients; Pattern; Phenotype; Play; Process; Publications; Regulation; Research Personnel; Research Proposals; Role; Signal Transduction; Signal Transduction Pathway; Structure; Surface; Surgical sutures; Syndrome; Tissues; Transducers; base; beta catenin; craniofacial; cranium; genetic linkage analysis; human disease; insight; intramembranous bone; malformation; member; migration; mutant; novel; osteoblast differentiation; osteoprogenitor cell; premature; programs; relating to nervous system; skeletal; skeletogenesis

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.

描述（由申请人提供）：该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。颅面形态发生受到表面和神经外胚层、内胚层、轴旁中胚层和颅神经嵴之间复杂相互作用的调节。这个过程高度依赖于移民颅神经嵴细胞的模式信息。大多数颅面部异常是由颅神经嵴细胞缺陷引起的，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，是最常见的人类先天性颅面畸形之一。颅缝早闭患者表现出颅骨异常，这是由颅骨缝和颅骨穹窿发育缺陷引起的。尽管遗传连锁分析提供了一些关于颅缝早闭相关综合征的分子基础的信息，但人们对颅缝和颅骨发育的生物学知之甚少。在本提案中，我们将研究介导转基因小鼠颅骨形态发生和颅缝早闭的基因调控网络。我们开发了几种独特适合这些研究的小鼠品系。 Axin2 突变严重影响颅骨组织和神经嵴起源结构的形成。突变体中出现了类似于人类颅缝早闭的表型缺陷。由于 Axin2 能够通过调节 β-连环蛋白的细胞水平来负调节 Wnt 通路，因此我们认为 Wnt-Axin 信号网络在颅骨形态发生中发挥着重要作用。我们将阐明由该信号网络介导的缝线发育的机制。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。