Regulation of Vertebrate Gonad Formation by Fibroblast Growth Factor Signaling

成纤维细胞生长因子信号传导对脊椎动物性腺形成的调节

• 批准号: 8886899
• 负责人: BRUCE W DRAPER
• 金额: $ 30.51万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886899
• 关键词: Accounting; Adult; Alleles; Americas; Cause of Death; Cell Maintenance; Cells; Data; Defect; Development; Developmental Process; Disease; Epithelial ovarian cancer; Etiology; Family; Fertility; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Functional disorder; Gene Expression; Genes; Genetic; Germ Cells; Goals; Gonadal structure; Growth; Histology; Human; Infertility; Laboratories; Lead; Ligands; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mammals; Mediating; Mission; Modeling; Molecular; Mutation; Ovary; Pathway interactions; Pattern; Play; Premature Ovarian Failure; Primordium; Process; Production; Public Health; Receptor Cell; Regulation; Research; Role; Secondary to; Signal Pathway; Signal Transduction; Somatic Cell; Specific qualifier value; Staging; System; Testing; Time; Undifferentiated; United States National Institutes of Health; Vertebrates; Woman; Women' s Role; Work; Zebrafish; angiogenesis; base; cell type; innovation; loss of function; mutant; novel; public health relevance; receptor; sex; zebrafish development

 DESCRIPTION (provided by applicant): Fibroblast growth factors (Fgf) signaling has been implicated in the progression of epithelial ovarian cancer, and numerous Fgf ligands and their receptors (Fgfr) are expressed in the developing and adult vertebrate gonads. However, the role of Fgf signaling in normal gonad development or function has only been defined in a limited context. Our long-term goal is to determine the roles Fgf signaling plays in gonad development, pathophysiology, and thus fertility, especially in the ovary. The objective of this application is o define the role Fgf signaling plays in the development of the early gonad primordium. Our entry point is the identification of a mutation in an Fgf ligand-encoding gene in zebrafish that results n rapid loss of germ cells during a stage when the somatic gonad primordium is forming. Our central hypothesis is that Fgf signaling is required for development of the early somatic gonad and that a somatic gonad defect in our Fgf mutant leads secondarily to loss of germ cells. This hypothesis has been formulated based on preliminary data from the applicant's laboratory. We will test this hypothesis by pursuing the following three Specific Aims: 1) Characterize the spatia requirement of Fgf signaling for development of the gonad primordium; 2) Determine the role of Fgf signaling in regulating the development of the early gonad; and 3) Determine which Fgf receptor(s) is required for development of the early zebrafish gonad. Based on our strong preliminary data, we hypothesize that the Fgf ligand is produced by the somatic cells of the early gonad primordium. Under the first aim we will determine in what cells the Fgf ligand is produced using genetic mosaic analysis. In the second aim, we will define what role the Fgf ligand plays in development of the gonad primordium by defining the developmental defect in our Fgf mutant. We will use a combination of histology, marker gene analysis and transcriptional profiling to test our hypothesis that Fgf signals promote and/or maintain the expression of genes that specify the early somatic gonad fate. Under our third aim we will define which cells respond to the Fgf ligand by determining the cognate Fgf receptor. This will allow us to define the mechanism by which Fgf signaling regulates early gonad development. We will use of loss-of-function, or when necessary, conditional mutations, in Fgf receptors to determine which are required for development of the early gonad. The proposed research is innovative because it utilizes a unique Fgf mutant that has enabled us to identify a novel role for Fgf signaling in early gonad development in the genetically amenable zebrafish system. The proposed research is significant because it will define a molecular pathway that regulates the development of the early gonad, and therefore is likely to identify how defects in Fgf signaling can account for cases of infertiliy or premature ovarian failure of unknown etiology in otherwise healthy women, and the role of Fgf signaling in gonad-originating cancers.

 描述（由适用提供）：在上皮卵巢癌的进展中暗示了成纤维细胞生长因子（FGF）信号传导，并且在发育中和成人脊椎动物性腺中表达了许多FGF配体及其受体及其受体（FGFR）。但是，FGF信号在正常性腺发育或功能中的作用仅在有限的环境中定义。我们的长期目标是确定FGF信号在性腺发育，病理生理学以及因此生育能力中的作用，尤其是在卵巢中。该应用的目的是o定义FGF信号在早期性腺基原始的发展中的作用。我们的切入点是鉴定斑马鱼中FGF配体编码基因中的突变，这在形成体细胞性腺形成的阶段会导致生殖细胞的快速损失。我们的中心假设是，FGF信号传导是早期的体细胞性腺发展所必需的，而我们的FGF突变体中的体细胞性腺缺陷导致生殖细胞丧失。该假设是根据申请人实验室的初步数据提出的。我们将通过追求以下三个特定目的来检验这一假设：1）表征FGF信号在性腺原始发展中的空中要求； 2）确定FGF信号传导在应对早期性腺发展中的作用； 3）确定早期斑马鱼性腺发展需要哪种FGF接收器。基于我们强大的初步数据，我们假设FGF配体是由早期性腺基原基的体细胞产生的。在第一个目的下，我们将使用遗传镶嵌分析来确定FGF配体的细胞。在第二个目标中，我们将通过定义FGF突变体中的发育缺陷来定义FGF配体在性腺原始中发挥什么作用。我们将使用组织学，标记基因分析和转录分析的组合来检验我们的假设，即FGF信号促进和/或维持指定早期体细胞性腺命运的基因的表达。在我们的第三个目标下，我们将通过确定同源FGF受体来定义哪些细胞对FGF配体的反应。这将使我们能够定义FGF信号调节早期性腺发育的机制。我们将在FGF接收器中使用功能丧失，或者在必要时使用条件突变，以确定早期性腺发育所需的哪些。拟议的研究具有创新性，因为它利用了一个独特的FGF突变体，该突变体使我们能够在遗传上可正约的斑马鱼系统中确定FGF信号传导的新作用。拟议的研究之所以重要，是因为它将定义一种调节早期性腺发展的分子途径，因此很可能会确定FGF信号中的缺陷如何解释其他健康女性中未知病因的非世俗或卵巢过早失败的病例，以及GONAD-GONAD-GONAD-GONAD-GONAD-ORIGINAD-ORIGIN-ORIGINECERINE CANCECERS的作用。