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Feedback Inhibitory Mechanisms in Skeletal Development

骨骼发育中的反馈抑制机制

基本信息

批准号：
7992748
负责人：
ROBERT E FRIESEL
金额：
$ 1.36万
依托单位：
MAINEHEALTH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7992748
关键词：
Adenoviruses Affect Apoptosis Biological Biological Process Calvaria Cell Proliferation Cephalic Chondrocytes Craniosynostosis Data Defect Development Differentiation and Growth Dominant-Negative Mutation Drosophila genus Ensure Equilibrium Exhibits FGFR1 gene FGFR2 gene Family Family member Feedback Fibroblast Growth Factor Fibroblast Growth Factor Receptors Frontal bone structure Gene Family Gene Targeting Growth and Development function Human In Vitro Investigation Laboratories Lead Limb Bud Mandible Maxilla Mediating Molecular Mouse Strains Mus Mutation Neural Crest Cell Nose Organ Culture Techniques Osteoblasts Outcome Output Pathway interactions Play Point Mutation Primordium Process Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Research Personnel Role Signal Pathway Signal Transduction Site Skeletal Development Skeletal system Structure Syndrome Technology Testing Tissues Transcription Factor AP-2 Alpha Transgenic Mice Vertebrates angiogenesis bone chondrodysplasia craniofacial in vivo inhibitor/antagonist insight knock-down loss of function member migration mouse development mouse model mutant osteoblast differentiation polypeptide programs recombinase research study response retroviral-mediated skeletal skeletal dysplasia skeletal tissue transcription factor tumorigenesis

项目摘要

The fibroblast growth factors (FGFs) and the fibroblast growth factor receptors (FGFRs) play important roles in development, including skeletal and craniofacial development. Activating mutations in human FGFR1, FGFR2, and FGFRS are associated with skeletal dysplasias including craniosynostosis and dwarfing syndromes. These mutations affect the proliferation and differentiation of osteoblasts and chondrocytes. These data indicate a pivotal role for FGFR signaling in skeletal development: signaling by FGFRs must be tightly regulated for normal development. Important unresolved issues are the identification of pathways activated by FGFRs during skeletal development, and how these pathways feedback to regulate FGF signaling. Studies in Drosophila and vertebrates have demonstrated that members of the Sprouty (Spry) gene family are inhibitors of FGFR signaling. Spryl, Spry2, and Spry4 are expressed in the limb buds, and maxillary and mandibular arches, as well as other sites during mouse development. Retroviral-mediated over-expression of Spryl in chick limb buds results in chondrodysplasia. We have developed a conditional transgenic mouse model to explore the role of Spry family members in skeletal development. We show that conditional expression of Spryl in cranial neural crest cells results in severe craniofacial defects including the absence of the nasal and frontal bones. These mice also exhibit greatly reduced expression of the transcription factors Msx1, Msx2, and AP2 in craniofacial primordia. We hypothesize that the function of Spry in skeletal development is to maintain a balance between FGF- mediated proliferation, differentiation, and apoptosis, and that the level of Spry expression determines this balance. Accordingly, we propose the following three specific aims: 1) to test the hypothesis that over- expression of Spry inhibits FGF activity in bone primordia, leading to decreased overall osteoblast development; 2) to use loss-of-function approaches to investigate the role of Spry in osteoblast proliferation, differentiation, and apoptosis in vivo; and 3) to characterize the mechanisms by which Spry affects osteoblast proliferation, differentiation, and apoptosis using calvarial cultures in vitro. These studies will provide significant insight into the negative regulation of signaling pathways in craniofacial and skeletal development and how perturbations in this feedback signaling pathway lead to skeletal dysplasias.

成纤维细胞生长因子（FGFs）和成纤维细胞生长因子受体（fgfr）在其中起着重要的作用