| Neurons that produce gonadotropin-releasing hormone (GnRH) are the central regulators of reproduction. GnRH is released from the hypothalamus to initiate and maintain fertility. The development of the GnRH neurosecretory system is a complex event that is presumably regulated by numerous chemical mediators. This dissertation focuses on the versatile actions fibroblast growth factor receptors (FGFRs) contribute to the formation of the GnRH secretory network. In embryos, GnRH neurons originate outside the central nervous system in the nasal placode. Subsequent relocation of GnRH neurons from the nasal region into the forebrain is one of the most striking examples of neuron migration. Once within the brain, GnRH neurons cease migrating and are found distributed through the preoptic and hypothalamic areas. From these regions, GnRH neurons must elaborate neurosecretory projections to contact the median eminence where GnRH is released. The pleiotropic roles of FGFR signaling in other neuronal systems provided the impetus to explore FGFR regulation in GnRH neuronal development.; FGFR signaling was investigated in three phases of GnRH neuron development: fate specification, migration and axon targeting to the median eminence. In mice, immunocytochemistry revealed FGFRs in embryonic GnRH neurons indicating GnRH neurons are capable of responding directly to FGF ligands. Fate specification studies in cultured nasal placode explants indicated FGFR signaling is essential for neuronal precursors to differentiate into GnRH neurons. GnRH neuron migration analysis revealed that migration into the brain was disrupted in transgenic mice engineered with reduced FGFR signaling specifically in their GnRH neurons (dnFGFR mice). In primary cultures, GnRH neurite outgrowth was mediated by FGFRs in wild-type GnRH neurons, but was reduced in dnFGFR. Further, tissues containing the median eminence cocultured with GnRH neurons attracted wild-type GnRH neurites, but failed to attract dnFGFR neurites; therefore, GnRH neurites target the median eminence in vitro via a FGFR-dependent mechanism. Collectively, these results demonstrated FGFR signaling regulates multiple phases of development in a neuroendocrine system essential for reproduction. Currently, these findings provide insight into the etiology of Kallmann syndrome, a human fertility disorder, likely the result of aberrant GnRH neuronal development and recently shown to be caused by mutations in the Fgfr1 gene. |
