FGF Signaling Pathways and Craniofacial Development

FGF 信号通路与颅面发育

• 批准号: 9911985
• 负责人: Philippe M Soriano
• 金额: $ 70.47万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-11 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911985
• 关键词: Alleles; Area; BCL2 gene; Binding; Biology; CRK gene; Cell Death; Cells; Cleft Palate; Cleft lip with or without cleft palate; Congenital Abnormality; Defect; Development; Dimerization; Drug Targeting; Embryo; Epithelial; Epithelial Cells; Epithelium; Epitopes; FGF10 gene; FGF7 gene; FGFR1 gene; FGFR2 gene; FRS2 gene; Face; Family; Feedback; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Funding; GRB14 gene; Gene Expression Profiling; Goals; Growth Factor; Human; Individual; Lateral; Ligand Binding; Ligands; MAPK3 gene; Mandible; Maxilla; Mediating; Mesenchymal; Mesenchyme; Molecular; Morphogenesis; Mus; Mutation; Neural Crest; Neural Crest Cell; Nose; Outcome; Pathway interactions; Pattern; Phenotype; Physiological; Play; Point Mutation; Population; Prevention; Process; Proteins; Proteomics; Role; Salivary Gland Diseases; Salivary Glands; Series; Signal Pathway; Signal Transduction; Specific qualifier value; Specificity; Structure; Tyrosine Phosphorylation Site; cell type; conditional mutant; craniofacial; craniofacial development; developmental disease; insight; migration; mutant; novel; prevent; receptor; response

The major aims of this proposal are to identify signaling mechanisms initiated by FGFs that underlie craniofacial morphogenesis. Loss of the FGFR1 receptor together with FGFR2 in neural crest cells leads to agenesis of multiple components of the midface and mandible, whereas hypomorphic mutations in Fgfr1/2 result in cleft palate. Elsewhere, FGFR2 rather than FGFR1 has a predominant role in salivary gland epithelia, and its activity is differentially regulated by various ligands. Engagement of the FGF signaling cascade leads to dimerization of the FGFRs, binding of multiple intracellular effectors and activation of cellular responses that converge on ERK1/2 and several other pathways. This application proposes: 1. To investigate how FGF signaling coordinates midface development. Combined loss of both Fgfr1 and Fgfr2 in neural crest cells leads to facial clefting that extends through the midline, agenesis of the midface, mandibular hypoplasia, and significant cell death in the lateral nasal and maxillary processes. To determine the origin of these midface defects, Fgfr1/2 mandibular and/or lateral nasal /maxillary process conditional mutants will be generated to investigate how loss of Fgfr1/2 in the mandible or lateral structures contributes to facial clefting. Furthermore, neural crest Fgfr1/2 mutants will be crossed to Bim mutants to disassociate alterations in patterning from BCL-2 family regulated cell death. 2. To identify signaling mechanisms promoted by Fgfr1 and Fgfr2 in craniofacial development. To identify signaling pathways that remain active in a previously generated Fgfr1 and Fgfr2 allelic series of point mutations that prevent the binding of single or multiple effector proteins and the initiation of specific signaling pathways, a proteomic screen will be performed in mouse embryonic palatal mesenchyme cells using endogenous epitope tagged FGFR1 and FGFR2 receptors. In a complementary approach, mice in which additional candidate tyrosine phosphorylation sites are disrupted on the receptors will be generated. 3. To characterize signaling pathways specified by ligand identity. An emerging theme in FGF signaling is that cellular responses in multiple physiological contexts can be encoded in the identity of the ligand and are not only specified at the level of the receptor. Signaling responses that are differentially encoded by FGF7 and FGF10 in submandibular salivary gland branching morphogenesis will be investigated. Critical downstream FGF pathways in this response will be further identified by transcriptional profiling following stimulation with each ligand, and morphogenetic responses that are sensitive to ERK1/2 and PI3K signaling and feedback inhibition pathways will be investigated. These proposed studies explore novel territories in the area of growth factor signaling in craniofacial biology and open new directions for the prevention of craniofacial birth defects.

这项建议的主要目的是确定信号机制发起的FGF的基础颅面 形态发生神经嵴细胞中FGFR 1受体和FGFR 2的缺失导致神经嵴细胞发育不全， 面中部和下颌骨的多个组成部分，而Fgfr 1/2的亚型突变导致裂 上颚在其他地方，FGFR 2而不是FGFR 1在唾液腺上皮中具有主导作用，并且其活性 受到不同配体的不同调节。FGF信号传导级联的参与导致FGF的二聚化。 FGFR、多种细胞内效应物的结合和细胞反应的激活， ERK 1/2和其他一些通路。本申请提出： 1.探讨FGF信号通路如何协调面中部发育。Fgfr 1和Fgfr 2的组合损失 在神经嵴细胞导致面裂延伸通过中线，发育不全的面中部，下颌 发育不全，以及侧鼻和上颌突中的显著细胞死亡。确定…的起源 这些面中部缺损，Fgfr 1/2下颌和/或侧鼻/上颌突条件突变体将被 研究下颌骨或侧部结构中Fgfr 1/2的缺失如何导致面裂。 此外，神经嵴Fgfr 1/2突变体将与Bim突变体杂交，以分离模式改变 BCL-2家族调节细胞死亡。 2.探讨Fgfr 1和Fgfr 2在颅面发育中的信号转导机制。以识别 在先前产生的Fgfr 1和Fgfr 2等位基因系列点突变中保持活性的信号通路 阻止单个或多个效应蛋白的结合和特异性信号通路的启动， 利用内源性表位在小鼠胚胎腭间充质细胞中进行蛋白质组学筛选 标记的FGFR 1和FGFR 2受体。在一种互补方法中，其中另外的候选酪氨酸 当磷酸化位点在受体上被破坏时，将产生。 3.表征配体特性指定的信号通路。成纤维细胞生长因子信号传导中的一个新主题是， 在多种生理环境中的细胞反应可以以配体的身份编码 在受体的水平上。由FGF 7和FGF 10差异编码的信号应答， 将研究下颌下唾液腺分支形态发生。关键下游FGF途径 在该应答中，将通过用每种配体刺激后的转录谱分析来进一步鉴定， 对ERK 1/2和PI 3 K信号传导和反馈抑制途径敏感的形态发生反应将 追究 这些拟议的研究探索了颅面生物学中生长因子信号传导领域的新领域， 为预防颅面出生缺陷开辟新的方向。