Gonadotropin-releasing hormone (GnRH) neuron migration: initiation, maintenance and cessation as critical steps to ensure normal reproductive function

Abstract

GnRH neurons follow a carefully orchestrated journey from their birth in the olfactory placode area. Initially, they migrate along with the vomeronasal nerve into the brain at the cribriform plate, then progress caudally to sites within the hypothalamus where they halt and send projections to the median eminence to activate pituitary gonadotropes. Many factors controlling this precise journey have been elucidated by the silencing or over-expression of candidate genes in mouse models. Importantly, a number of these factors may not only play a role in normal physiology of the hypothalamic-pituitary-gonadal axis but also be mis-expressed to cause human disorders of GnRH deficiency, presenting as a failure to undergo normal pubertal development. This review outlines the current cadre of candidates thought to modulate GnRH neuronal migration. The further elucidation and characterization of these factors that impact GnRH neuron development may shed new light on human reproductive disorders and provide potential targets to develop new pro-fertility or contraceptive agents.

Figure 1

Heparan sulfate proteoglycans: role in modulating ligand activation of membrane receptors. Expanding data suggests that certain ligands or their receptors with fibonectin domains or similar regions are modulated by classes of heparan sulfate proteoglycans (HSPGs) (eg. in c. elegans, syndecan-1 or glipican-1) with specific HS to control ligand activation. These include potential interactions with Gas6/Axl or Tyro3 and documented interactions with HGF/cMET, netrin/DCC, FGF8/FGFR1, anosmin and PROK2/PROKR2.

Figure 2

Crosstalk between membrane receptors targeting of olfactory nerves and migration of GnRH neurons. HGF/Met, chemokine and Semaphorin pathways have been implicated in both olfactory nerve targeting and GnRH neuron migration. SDF-1 (CXCL12) chemokine and its receptor CXCR4 may interact with HGF (hepatocyte growth factor)/cMET which in turn may interact with semaphorins and their plexin receptors in the absence or presence of docking intermediates NP2 (neuropilin 2).