GENETIC REGULATORY NETWORK IN CRANIOFACIAL DEVELOPMENT

颅面发育中的遗传调控网络

• 批准号: 7626374
• 负责人: Wei Hsu
• 金额: $ 34.38万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626374
• 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。颅面形态发生受表面和神经外胚层，内胚层，近去中胚层和颅神经rest之间的复杂相互作用的调节。该过程高度依赖于移民颅神经rest细胞的模式信息。大多数颅面异常是由颅神经rest细胞缺陷引起的，这些缺陷引起了包括颅骨在内的各种面部组织和结构。颅骨突变影响约2500名婴儿，是最常见的人类先天颅颅畸形中的1个。颅骨突变病的患者表现出异常的瓦尔瓦里亚，这是由于颅骨缝合线和头骨穹顶发育的缺陷引起的。尽管遗传连锁分析提供了有关颅突变相关综合征的分子基础的一些信息，但对缝合线和颅骨发育的生物学知之甚少。在此提案中，我们将研究介导循环修饰的小鼠中钙化形态发生和颅突变的遗传调节网络。我们已经开发了几种非常适合这些研究的小鼠菌株。 AXIN2的突变严重影响了颅骨组织的形成和神经rest的结构。表型缺陷类似于突变体发展的人类中的颅突。由于AXIN2通过调节β-catenin的细胞水平来负调节WNT途径的能力，因此我们建议Wnt-X-XKIN信号网络在钙化形态发生中起重要作用。我们将阐明该信号网络介导的缝合缝合开发机制。这些研究有助于对颅面发育和人类疾病的分子机制的新见解。