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; 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（由应用程序提供）：该提案继续我们努力阐明颅面发展的遗传调节网络。颅面骨架由内脏乳腺癌和神经乳骨组成，这些骨骼被细分为钙/颅骨库和软骨群/颅底。在钙钙的发育过程中，颅缝合线是骨骼生成的生长中心。缝合形态发生的缺陷导致过早闭合，尽管人类遗传分析已经鉴定出与这些疾病发病机理有关的基因，但对缝合闭合的调节鲜为人知，这对于发展健康的头骨至关重要。在先前提出的研究中，我们通过表明AXIN2缺陷小鼠表现出类似于人类的颅骨so症的缝合力缺陷，将典型的Wnt途径与钙钙化的发育联系起来。 AXIN2/�-蛋白质信号传导调节缝合干细胞的膨胀及其随后的发育过程。 AXIN2的敲除还导致诱导与突触相关的基因，包括编码FGF受体家族成员的基因。这些基因中的突变与人类和小鼠中的联合综合症有关。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承诺至关重要。结果确定了通过切换干细胞命运而引起的内侧软骨骨化是在发育过程中缝合闭合的机制，并在颅突式症中隐含了这一过程。我们的发现导致我们提出了一个模型，其中Wnt，FGF和BMP信号的相互作用对于策划钙化形态发生调节网络至关重要。在此提案中，我们将继续阐明这些途径由健康和疾病中的途径协调介导的钙化形态发生的机制。设计三个特定的目的是：1）将BMP信号传导的作用定义为缝合间充质开发中确定的关键； 2）阐明了BMP串扰和FGF信号传导的机制； 3）确定GPR177在WNT介导的颅面骨骼发展中的作用。