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.
The proposed research is relevant to public health because defects in gonad development can lead to infertility or premature ovarian failure in otherwise healthy women. In addition, aberrant fibroblast growth factor (Fgf) signaling is associated with aggressive ovarian cancer, which is estimated to cause the death of 14,000 America women in 2013. Therefore, understanding the roles of Fgf signaling during normal gonad development is relevant to the NIH mission, as it will lead to better identification and treatment of diseases.
| Draper, Bruce W (2017) Identification of Germ-Line Stem Cells in Zebrafish. Methods Mol Biol 1463:103-113 |
| Leerberg, Dena M; Sano, Kaori; Draper, Bruce W (2017) Fibroblast growth factor signaling is required for early somatic gonad development in zebrafish. PLoS Genet 13:e1006993 |
| Yan, Yi-Lin; Desvignes, Thomas; Bremiller, Ruth et al. (2017) Gonadal soma controls ovarian follicle proliferation through Gsdf in zebrafish. Dev Dyn 246:925-945 |
