Role of fibroblast growth factor signaling in gonadotropin-releasing hormone neuronal system development

Abstract

There is growing evidence demonstrating that fibroblast growth factor (FGF) signaling is important for the development of the gonadotropin-releasing hormone (GnRH) neuronal system. In humans, loss-of-function mutations in FGF receptor 1 (Fgfr1) and Fgf8 lead to hypogonadotropic hypogonadism (HH) with or without anosmia. Insights into how FGF signaling deficiency disrupts the GnRH system in humans are beginning to emerge from studies using transgenic mouse models. In this review, we summarize GnRH system defects in several lines of FGF signaling-deficient mice. We showed that FGF signaling is critically required for olfactory placode induction, differentiation, and GnRH neuronal fate specification and postnatal maintenance. Extrapolating from these transgenic mouse data, we suggest that idiopathic HH in patients harboring loss-of-function Fgfr1 and/or Fgf8 mutations is not merely a result of defective GnRH neuronal migration, but also insults accumulated in the GnRH system during fate specification and postnatal development.

Fig. 1

Parasagittal schematic representation of the mouse olfactory placode (red) on E11.5. The secondary recess (arrow) in the olfactory placode, from where the GnRH neurons (blue) emerge, is present in the wild-type, but not in the homozygous Fgf8 hypomorphic embryo. This suggests that the formation of this recess is FGF8 dependent. FGF8 signaling is also important for the development of the peripherin-positive fibers (green) of the VNN, which fail to enter the homozygous Fgf8 hypomorphic mouse forebrain. However, because GnRH neurons were eliminated prior to entering the migrational phase, we hypothesize that the primary impact of FGF8 deficiency is upon the fate specification process of GnRH neurons.