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）：本提案的主要目的是确定由FGF启动的信号传导机制，这些机制是腭和面中部正常发育的基础。两种受体Fgfr 1和Fgfr 2的条件性缺失导致多发性颅面缺损。虽然FGF信号已被广泛研究，从生化的角度在许多实验室，包括我们自己的，显着很少知道这些信号通路如何调节颅面发育的形态发生过程。在本申请中，我们提出：1.探讨腭上皮中FGF信号通路的调控。上皮中Fgfr 2的缺失导致腭裂。为了建立这种缺陷背后的信号机制，我们将产生和分析一系列等位基因的条件信号小鼠突变体的Fgfr 2基因座，防止单一或多个效应蛋白的结合。我们将进一步表征腭上皮中Fgfr 2信号传导的转录靶点，并确定它们是否可以调节底层间充质的后续增殖。2.探讨FGF信号在神经嵴中的调控途径。神经嵴中Fgfr 1的缺失导致多种颅面缺损，包括腭闭合。为了确定潜在的信号传导机制，我们将在Fgfr 1位点产生并表征一系列条件信号传导小鼠突变体的等位基因，这些突变体阻止单个或多个效应蛋白的结合，靶向与Fgfr 2相同的途径。由于腭和其他颅面器官来源于从背神经外胚层迁移的神经嵴细胞，我们还将进行基于Cre的谱系分析，以表征突变表型背后的神经嵴细胞迁移缺陷。3.确定和表征控制额鼻发育的FGF调节途径。神经嵴细胞中Fgfr 1和Fgfr 2的联合缺失导致延伸至中线的面部裂。建立 为了确定这种表型的机制基础，我们将在神经嵴细胞中用携带相同效应子点突变的复合Fgfr 1和Fgfr 2条件突变体进行条件诱变，并将其与双无效突变体进行比较。我们将通过条件突变，特别是在额鼻突，进一步建立FGF信号传导在面中部发育中的作用。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FGF发挥作用的信号传导机制，并通过可能应用关键FGF细胞内效应物的药物靶点为预防颅面出生缺陷开辟新方向。 公共卫生相关性：包括唇腭裂在内的颅面发育性疾病是全球人口中最常见的出生缺陷。这项建议的主要目的是确定FGF信号控制的机制，这些机制是面中部正常发育的基础。我们将确定下游FGF细胞内信号通路，是至关重要的中线发展，研究FGF信号在上皮细胞和神经嵴细胞，并分析FGF受体突变体的额鼻过程的发展。