FGF Signaling Pathways and Craniofacial Development

FGF 信号通路与颅面发育

• 批准号: 8343550
• 负责人: Philippe M Soriano
• 金额: $ 62.67万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8343550
• 关键词: Alleles; Area; Auditory; Binding; Biochemical; Biology; Cephalic; Cleft Lip; Cleft Palate; Congenital Abnormality; Defect; Development; Dimerization; Disease; Dorsal; Drug Delivery Systems; Ectoderm; Epithelium; Face; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Targeting; Growth Factor; Human; Individual; Laboratories; Lead; Mesenchymal; Mesenchyme; Mus; Mutagenesis; Mutant Strains Mice; Mutation; Neural Crest; Neural Crest Cell; Organ; Palate; Pathway interactions; Phenotype; Play; Point Mutation; Population; Prevention; Process; Proteins; Role; Series; Signal Pathway; Signal Transduction; Tissues; base; bone; cell motility; cell type; craniofacial; migration; mutant; neoplastic; novel; prevent; receptor; relating to nervous system; response; skeletal disorder

DESCRIPTION (provided by applicant): The major aims of this proposal are to identify signaling mechanisms initiated by FGFs that underlie normal development of the palate and the midface. Conditional deletion of the two receptors Fgfr1 and Fgfr2 lead to multiple craniofacial defects. Although FGF signaling has been extensively studied from a biochemical standpoint in many laboratories, including our own, remarkably little is known about how these signaling pathways regulate morphogenetic processes in craniofacial development. In this application, we propose: 1. To investigate the pathways regulated by FGF signaling in the palatal epithelium. Loss of Fgfr2 in the epithelium leads to a cleft palate. To establish the signaling mechanisms underlying this defect, we will generate and analyze an allelic series of conditional signaling mouse mutants at the Fgfr2 locus that prevent the binding of single or multiple effector proteins. We will further characterize transcriptional targets of Fgfr2 signaling in the palatal epithelium and determine if they can regulate subsequent proliferation of the underlying mesenchyme. 2. To investigate the pathways regulated by FGF signaling in the neural crest. Loss of Fgfr1 in the neural crest leads to multiple craniofacial defects, including in palate closure. To identify the underlying signaling mechanisms, we will generate and characterize an allelic series of conditional signaling mouse mutants at the Fgfr1 locus that prevent the binding of single or multiple effectors proteins, targeting the same pathways as for Fgfr2. Since the palate and other craniofacial organs are derived from neural crest cells migrated from dorsal neural ectoderm, we will also conduct Cre based lineage analysis to characterize defects in neural crest cell migration that underlie the mutant phenotypes. 3. To identify and characterize the FGF regulated pathways that control frontonasal development. Combined loss of both Fgfr1 and Fgfr2 in neural crest cells leads to facial clefting that extends through the midline. To establish the mechanistic basis for this phenotype, we will perform conditional mutagenesis in neural crest cells with compound Fgfr1 and Fgfr2 conditional mutants carrying point mutations for identical effectors, and compare these to the double null mutants. We will further establish the role of FGF signaling in midface development by conditional mutagenesis specifically in the frontonasal process. The proposed studies are anticipated to have a significant impact in craniofacial biology because they will establish the signaling mechanisms by which FGFs exert their action and open new directions for the prevention of craniofacial birth defects by the possible application of drug targets for critical FGF intracellular effectors. PUBLIC HEALTH RELEVANCE: Craniofacial developmental diseases including cleft lip or palate are the most prevalent birth defects in the human population worldwide. The major aims of this proposal are to identify mechanisms controlled by FGF signaling that underlie normal development of the midface. We will identify downstream FGF intracellular signaling pathways that are critical in midline development, investigate how FGFs signal in the epithelium and in neural crest cells, and analyze the development of the frontonasal process in FGF receptor mutants.

描述（由申请人提供）：该提案的主要目的是确定FGF发起的信号传导机制，这些信号机制是pa和中间正常发育的基础。两个受体FGFR1和FGFR2的条件缺失导致多个颅面缺陷。尽管从许多实验室的生化角度进行了广泛研究FGF信号传导，包括我们自己的，但对于这些信号通路如何调节颅面发育中的形态发生过程的知之甚少。在此应用中，我们提出：1。研究palatal上皮中FGF信号传导调节的途径。上皮中FGFR2的损失导致口感裂。为了建立该缺陷的基础信号机制，我们将在FGFR2基因座上生成和分析一系列等位基因信号传导小鼠突变体，以防止单个或多个效应子蛋白的结合。我们将进一步表征palatal上皮中FGFR2信号传导的转录靶标，并确定它们是否可以调节下面间质的随后增殖。 2。研究神经波峰中FGF信号传导调节的途径。神经rest中FGFR1的丧失导致多个颅面缺陷，包括口感闭合。为了识别潜在的信号机制，我们将在FGFR1基因座处生成和表征一系列等位基因信号小鼠突变体，以防止单个或多个效应子蛋白的结合，以与FGFR2相同的途径。由于味觉和其他颅面器官是从迁移从背侧神经外胚层迁移的神经rest细胞中得出的，因此我们还将进行基于CRE的谱系分析，以表征突变表型基于突变表型的神经纹rest细胞迁移中的缺陷。 3。识别和表征控制额骨发展的FGF调节途径。神经rest细胞中FGFR1和FGFR2的联合损失导致面部裂纹延伸到中线。建立 在这种表型的机理基础上，我们将在具有相同效应子的复合FGFR1和FGFR2条件突变体的神经rest细胞中进行有条件的诱变，并将其与双重零突变体进行比较。我们将进一步确定FGF信号在额骨过程中专门通过条件诱变中的中心发育中的作用。预计拟议的研究将对颅面生物学产生重大影响，因为它们将建立FGFS通过可能应用药物靶标在关键的FGF内细胞内效应子中应用药物靶标的颅面生育缺陷的信号传导机制。 公共卫生相关性：包括唇裂或pa裂在内的颅面发育疾病是全球人口中最普遍的先天缺陷。该提案的主要目的是确定由FGF信号控制的机制，这些机制是中间正常发展的基础。我们将确定在中线发育中至关重要的下游FGF细胞内信号通路，研究上皮中FGF的信号如何信号，并分析FGF受体突变体中额骨过程的发展。