Genetic Regulatory Network in Craniofacial Development

颅面发育中的遗传调控网络

• 批准号: 8481531
• 负责人: Wei Hsu
• 金额: $ 37.08万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8481531
• 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; Little' s Disease; 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; 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

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（由申请人提供）：该提案继续努力阐明颅面发育的基因调控网络。颅面骨骼由内脏颅骨和神经颅骨组成，在颅骨发育过程中又分为颅骨/颅骨穹窿和软骨颅骨/颅底。颅骨、颅缝作为骨骼发生的生长中心。缝线形态发生的缺陷。导致过早闭合的疾病与人类先天性颅面畸形有因果关系，尽管人类基因分析已经确定了与这些疾病发病机制有关的基因，但人们对缝线闭合的调节知之甚少，而缝线闭合对于健康颅骨的发育至关重要。在这项研究中，我们发现 Axin2 缺陷小鼠表现出类似于人类颅缝早闭的缝合缺陷，从而将经典 Wnt 通路与颅骨发育联系起来。 -连环蛋白信号传导调节缝合干细胞的扩增及其随后的发育过程，Axin2 的敲除也会导致与骨连接相关的基因的诱导，包括那些编码 FGF 受体家族成员的基因。这些基因的突变与骨连接相关。我们进一步表明，Wnt 和 FGF 的平衡对于确定颅骨发育过程中缝合干细胞的谱系定向至关重要。改变干细胞命运作为发育过程中缝线闭合的机制，并将这一过程与颅缝早闭相关联，我们的研究结果使我们提出了一个模型，其中 Wnt、FGF 和 BMP 信号传导的相互作用对于协调颅骨形态发生调节网络至关重要。在本提案中，我们将继续阐明这些通路在健康和疾病中协调介导的颅骨形态发生的机制，旨在：1）定义 BMP 信号传导的作用。作为缝合间质发育的关键决定因素；2) 阐明颅骨形态发生中 BMP 和 FGF 信号串扰的机制；3) 确定 Gpr177 在 Wnt 介导的颅面骨骼发育中的作用。