Genetic Regulatory Network in Craniofacial Development

颅面发育中的遗传调控网络

• 批准号: 8291784
• 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/8291784
• 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. PUBLIC HEALTH RELEVANCE: This proposal investigates the basic genetic elements controlling the formation of a healthy skull during craniofacial skeletogenesis. Using genetically modified mouse strains, we elucidate the mechanism underlying the interplay of three evolutionary conserved signal transduction pathways in normal development and pathogenesis of the skull vault. The results obtained in our study are highly relevant to the health of human development in craniofacial deformities, such as craniosynostosis and cleiocranial dysplasia, and has potentials to gain insights into therapeutic strategies for human diseases.

描述（由申请人提供）：该提案继续我们的努力，以阐明颅面发育的遗传调控网络。颅面骨骼由脏颅和脑颅组成，脑颅又分为颅骨/颅骨穹窿和软骨颅/颅底。在颅骨的发育过程中，颅缝是骨骼发生的生长中心。导致过早闭合的缝线形态发生缺陷与人类先天性颅面畸形有因果关系。虽然人类遗传分析已经确定了参与这些疾病发病机制的基因，但对健康颅骨发育所必需的缝闭合调节知之甚少。在先前提出的研究中，我们通过显示Axin 2缺陷小鼠表现出类似于人类颅缝早闭的缝合缺陷，将经典Wnt通路与颅骨发育联系起来。Axin 2/β-catenin信号调节缝线干细胞的扩增及其随后的发育过程。Axin 2的敲除还导致骨结合相关基因的诱导，包括编码FGF受体家族成员的那些基因。这些基因的突变与人类和小鼠的骨性结合相关综合征有关。我们进一步表明，Wnt和FGF的平衡是必不可少的，以确定在颅骨发育过程中的缝干细胞的谱系承诺。研究结果确定了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，并暗示了这一过程与颅缝早闭有关。我们的研究结果使我们提出了一个模型，其中Wnt，FGF和BMP信号的相互作用是必不可少的协调颅骨形态发生调控网络。在这个建议中，我们将继续阐明这些途径在健康和疾病中协调介导的颅骨形态发生的机制。设计了三个具体目标：1）定义BMP信号传导作为缝间充质发育中的关键决定因素的作用; 2）阐明颅骨形态发生中BMP和FGF信号传导串扰的潜在机制; 3）确定Gpr 177在Wnt介导的颅面骨骼发育中的作用。 公共卫生关系：该建议调查了在颅面骨骼发生过程中控制健康头骨形成的基本遗传因素。使用转基因小鼠品系，我们阐明了三个进化保守的信号转导通路在正常发育和发病机制的颅骨穹窿的相互作用的机制。我们的研究结果与颅面畸形（如颅缝早闭和锁骨发育不良）的人类发育健康高度相关，并有可能深入了解人类疾病的治疗策略。