Genetic Regulatory Network in Craniofacial Development

颅面发育中的遗传调控网络

基本信息

批准号：
9057505
负责人：
Wei Hsu
金额：
$ 38.63万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9057505
关键词：
Affect Apoptosis BMPR1A gene Bone Morphogenetic Proteins Calvaria Cells Cephalic Chondrocranium Chondrocytes Congenital abnormal Synostosis Craniosynostosis Defect Deformity Development Developmental Process Disease Drosophila genus Dysplasia Equilibrium Exhibits Family Fibroblast Growth Factor Fibroblast Growth Factor Receptors Genes Genetic Growth Health Human Human Development Human Genetics Individual Influentials Investigation Jaw Joint structure of suture of skull Knock-out Lead Link MAP Kinase Gene Mediating Mediator of activation protein Mesenchymal Mesenchyme Modeling Monomeric GTP-Binding Proteins Morphogenesis Mouse Strains Mus Mutation Osteoblasts Pathogenesis Pathway interactions Phenotype Population Process Production Proteomics Receptor Signaling Regulation Role Signal Transduction Signal Transduction Pathway Skeletal Development Skeleton Source Staging Stem cells Surgical sutures Syndrome Testing Therapeutic Wnt proteins bone cell type craniofacial craniofacial development cranium design genetic analysis genetic element human disease insight intramembranous bone formation member mouse model mutant postnatal precursor cell premature receptor skeletal skeletal disorder skeletogenesis skull base stem cell fate stem cell population

项目摘要

DESCRIPTION (provided by applicant): This proposal continues our efforts to elucidate the genetic regulatory network underlying craniofacial development. The craniofacial skeleton consists of viscerocranium and neurocranium, which is subdivided into the calvarium/skull vault and chondrocranium/skull base. During development of the calvarium, cranial sutures serve as growth centers for skeletogenesis. Defects in suture morphogenesis resulting in premature closure are causally linked to congenital craniofacial deformities in humans. Although human genetic analyses have identified genes involved in pathogenesis of these diseases, little is known about the regulation of suture closure which is essential for development of a healthy skull. In the previously proposed investigation, we have linked the canonical Wnt pathway to calvarial development by showing that Axin2-deficient mice exhibit suture defects resembling craniosynostosis in humans. Axin2/¿-catenin signaling regulates the expansion of suture stem cells and their subsequent developmental processes. Knockout of Axin2 also results in induction of the synostosis-related genes, including those encoding members of the FGF receptor family. Mutations in these genes have been linked to synostosis-related syndromes in humans and mice. We have further shown that the balance of Wnt and FGF is essential for determining the lineage commitment of suture stem cells during calvarial development. The results identify endochondral ossification caused by switching the stem cell fate as a mechanism of suture closure during development and implicate this process in craniosynostosis. Our findings have led us to propose a model in which the interplay of Wnt, FGF and BMP signaling is essential for orchestrating the calvarial morphogenetic regulatory network. In this proposal, we will continue to elucidate the mechanism underlying calvarial morphogenesis coordinately mediated by these pathways in health and disease. Three specific aims are designed to: 1) define the role of BMP signaling as a key determinant in development of suture mesenchyme; 2) elucidate the mechanism underlying the crosstalk of BMP and FGF signaling in calvarial morphogenesis; 3) determine the role of Gpr177 in Wnt-mediated development of craniofacial skeleton.

描述（由申请人证明）：该提案继续进行遗传调节性，颅面骨骼由内脏骨骼组成，该骨骼被细分为钙 /颅骨库中的calvarium /skull base。 Cloure与人类的先天性颅骨相结合，对缝合线的调节鲜为人知，这对于健康的颅骨发育至关重要/¿ - 依宁氨酸氨酸氨酸氨酸氨酸氨酸氨酸氨酸氨酸氨酸氨酸氨酸氨酸氨酸氨酸氨酸氨酸2 axin2 ALSOLT诱导与Synostos相关的基因诱导的基因，包括fgf受体家族的那些属于IS-IS-IS-IS-IS-IS FORGENINF，缝合线缝合缝合物在发育过程中，缝合线的缝合力是通过切换的缝合力来确定干细胞命运在发育过程中的缝合力机制通过健康的三个途径，并解散了：1定义BMP信号传导作为缝合线质的关键发育，D fgf信号在钙化的形态发生中；