Fibroblast growth factor 8 signaling through fibroblast growth factor receptor 1 is required for the emergence of gonadotropin-releasing hormone neurons

Endocrinology. 2008 Oct;149(10):4997-5003. doi: 10.1210/en.2007-1634. Epub 2008 Jun 19.

Abstract

GnRH neurons are essential for the onset and maintenance of reproduction. Mutations in both fibroblast growth factor receptor (Fgfr1) and Fgf8 have been shown to cause Kallmann syndrome, a disease characterized by hypogonadotropic hypogonadism and anosmia, indicating that FGF signaling is indispensable for the formation of a functional GnRH system. Presently it is unclear which stage of GnRH neuronal development is most impacted by FGF signaling deficiency. GnRH neurons express both FGFR1 and -3; thus, it is also unclear whether FGFR1 or FGFR3 contributes directly to GnRH system development. In this study, we examined the developing GnRH system in mice deficient in FGF8, FGFR1, or FGFR3 to elucidate the individual contribution of these FGF signaling components. Our results show that the early emergence of GnRH neurons from the embryonic olfactory placode requires FGF8 signaling, which is mediated through FGFR1, not FGFR3. These data provide compelling evidence that the developing GnRH system is exquisitely sensitive to reduced levels of FGF signaling. Furthermore, Kallmann syndrome stemming from FGF signaling deficiency may be due primarily to defects in early GnRH neuronal development prior to their migration into the forebrain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cell Movement / physiology
  • Fibroblast Growth Factor 8 / metabolism*
  • Gene Expression Regulation, Developmental
  • Gonadotropin-Releasing Hormone / physiology*
  • Hypothalamus / cytology
  • Hypothalamus / embryology
  • Hypothalamus / physiology
  • Intermediate Filament Proteins / metabolism
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / metabolism
  • Neurons / physiology
  • Olfactory Pathways / cytology
  • Olfactory Pathways / embryology*
  • Olfactory Pathways / physiology*
  • Peripherins
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism
  • Vomeronasal Organ / cytology
  • Vomeronasal Organ / embryology
  • Vomeronasal Organ / physiology

Substances

  • Ebf1 protein, mouse
  • Fgf8 protein, mouse
  • Intermediate Filament Proteins
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • Peripherins
  • Trans-Activators
  • Fibroblast Growth Factor 8
  • Gonadotropin-Releasing Hormone
  • Fgfr1 protein, mouse
  • Fgfr3 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Fibroblast Growth Factor, Type 3