Genetic Regulatory Network in Craniofacial Development

颅面发育中的遗传调控网络

• 批准号: 8667323
• 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
• 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/8667323
• 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; 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)：这项建议继续我们的努力，以阐明潜在的头面部发育的基因调控网络。颅面骨架由内脏颅骨和脑颅组成，又分为颅骨/颅顶和软骨/颅底。在颅骨发育过程中，颅缝是骨骼形成的生长中心。缝线形态发生缺陷导致的过早闭合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的发病机制有关的基因，但对缝合的调节知之甚少，缝合闭合对于健康的头骨发育至关重要。在之前提出的研究中，我们通过显示Axin2缺陷小鼠表现出类似于人类颅缝融合的缝合缺陷，将典型的Wnt途径与颅骨发育联系起来。Axin2/？-catenin信号调节缝合干细胞的扩张及其随后的发育过程。Axin2基因的敲除也导致了与融合相关的基因的诱导，包括那些编码成纤维细胞生长因子受体家族成员的基因。这些基因的突变被认为与人类和小鼠的联会相关综合征有关。我们进一步证明，在颅骨发育过程中，Wnt和成纤维细胞生长因子的平衡对于决定缝合干细胞的谱系承诺至关重要。研究结果表明，由干细胞命运转换引起的软骨内骨化是发育过程中缝合闭合的一种机制，并暗示这一过程与颅缝融合有关。我们的发现导致我们提出了一个模型，在该模型中，Wnt、成纤维细胞生长因子和BMP信号的相互作用对于协调颅骨形态发生调控网络是必不可少的。在这项提案中，我们将继续阐明这些途径在健康和疾病中协调调节的颅骨形态发生的潜在机制。我们设计了三个特定的目标：1)明确BMP信号在缝合间充质发育中的关键决定因素；2)阐明BMP和成纤维细胞生长因子信号在颅骨形态发生中的相互作用的机制；3)确定Gpr177在Wnt介导的头面部骨骼发育中的作用。