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.

该提案的主要目的是确定基于颅面的FGF发起的信号传导机制 形态发生。 FGFR1受体的丧失与FGFR2在神经rest细胞中的丧失导致发病 中间和下颌骨的多个成分 口感。在其他地方，FGFR2而不是FGFR1在唾液腺上皮中具有主要作用，其活性 由各种配体差异调节。 FGF信号级联的参与导致 FGFR，多个细胞内效应子的结合以及在收敛上的细胞反应的激活 ERK1/2和其他几个途径。本申请提出： 1。研究FGF信号如何坐在中间的开发。 FGFR1和FGFR2的总损失 在神经rest细胞中，导致面部裂纹延伸到中线，中间的发育膜，下颌 下鼻和上颌过程中的低流质和明显的细胞死亡。确定起源 这些中间缺陷，FGFR1/2下颌和/或外侧鼻/上颌过程条件突变体将是 生成的是研究下颌骨或横向结构中FGFR1/2的损失如何有助于面部裂纹。 此外，神经Crest FGFR1/2突变体将被交叉至BIM突变体，以分离模式的变化 来自Bcl-2家族调节的细胞死亡。 2。确定FGFR1和FGFR2在颅面发育中促进的信号传导机制。识别 在先前生成的FGFR1和FGFR2等位基因突变中保持活跃的信号通路 这可以防止单个或多个效应子蛋白的结合以及特定信号通路的启动 蛋白质组学筛选将使用内源性表位在小鼠胚胎palatal间充质细胞中进行 标记的FGFR1和FGFR2受体。在互补的方法中，小鼠在其中其他候选酪氨酸 将在受体上破坏磷酸化位点。 3。表征配体身份指定的信号通路。 FGF信号中的一个新兴主题是 在多种生理环境中的细胞反应可以在配体的身份中编码，不仅是 在受体的水平上指定。由FGF7和FGF10差异编码的信号响应 下颌下唾液腺分支形态发生。关键下游FGF途径 在此响应中，将通过对每个配体刺激后的转录分析进一步识别，并且 对ERK1/2敏感的形态发生反应，PI3K信号传导和反馈抑制途径将 被调查。 这些拟议的研究探讨了颅面生物学和 开放预防颅面先天缺陷的新方向。