Developmental Regulation of Gonadotropin-Releasing Hormone Neurons by Fibroblast Growth Factor Signaling

• Published in: Endocrinology (Philadelphia) 2004-08, Vol.145 (8), p.3830-3839
• Main Authors: Gill, John C, Moenter, Suzanne M, Tsai, Pei-San
• Format: Article
• Language: English
• Subjects: Animals; Axon guidance; Axonogenesis; Biological and medical sciences; Cells, Cultured; Embryogenesis; Female; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - pharmacology; Fibroblast growth factors; Fibroblast Growth Factors - pharmacology; Fibroblasts; Fluorescence; Fundamental and applied biological sciences. Psychology; Gonadotropin-releasing hormone; Gonadotropin-Releasing Hormone - physiology; Gonadotropins; Green fluorescent protein; Growth factors; Immunocytochemistry; Mice; Mice, Inbred Strains; Neurites - drug effects; Neurites - physiology; Neuroendocrine system; Neurons; Neurons - physiology; Neurotrophic factors; Pituitary (anterior); Pyrroles - pharmacology; Receptor mechanisms; Receptors, Fibroblast Growth Factor - analysis; Receptors, Fibroblast Growth Factor - physiology; Reproduction; Signal Transduction; Vertebrates; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2004-0214

GnRH neurons are central to the initiation and maintenance of reproductive function in diverse vertebrates. The formation of a functional GnRH system during development is a highly complex event that likely requires extensive guidance by neurotrophic factors. In this study, we examined whether members of the fibroblast growth factor (FGF) family are critically involved in the development of endogenous GnRH neurons. Immunocytochemistry revealed the presence of FGF receptors (FGFRs) 1, 2, and 3, but not 4, in embryonic day (E) 10.5 medial nasal placode, an area and time consistent with the first appearance of GnRH neurons in mice. Dual immunocytochemistry confirmed the presence of FGFRs 1 and 3, but not 2 and 4, in a substantial fraction of E15.5 and postnatal day (P) 3 GnRH neurons. To examine whether FGF signaling was essential for the specification of GnRH neuronal fate, a nasal explant culture that supported the in vitro emergence of GnRH neurons from E10.5 noses was established. In this system, the addition of SU5402, a FGFR antagonist, suppressed the emergence of GnRH neurons. Lastly, we investigated whether FGF signaling altered the extension of neurites in cultures of dispersed GnRH neurons. The addition of FGF2 to E15.5 and P3 GnRH neurons expressing the green fluorescent protein significantly stimulated neurite outgrowth (E15.5 and P3) and branching (P3), suggesting a regulatory role of FGFs in GnRH axon targeting. Together these results demonstrated that FGF signaling critically regulates multiple phases of development in a neuroendocrine system essential for vertebrate reproduction.