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 profertility or contraceptive agents. IntroductionGonadotropin-releasing hormone (GnRH) is a hypothalamic releasing hormone that is synthesized in a small heterogenous neuronal population and secreted in an episodic fashion to control pituitary gonadotropin production and normal reproductive function(1-5). The GnRH neurons are unique among hypothalamic releasing factor neurons in that they originate in the olfactory placode/vomeronasal organ and migrate along vomeronasal nerves to the cribriform plate, the boundary between the peripheral olfactory system and the forebrain(1-5). Migrating GnRH neurons follow a branch of the vomeronasal nerve caudally into the hypothalamus(4). They then extend processes to the median eminence to release GnRH into the capillaries of the median eminence to modulate pituitary gonadotropin (luteinizing hormone, LH and follicle stimulating hormone, FSH) production and secretion. Loss of these neurons or misdirecting along the route results in failure of sexual maturation in mice and man. The underlying mechanisms that regulate the migration of GnRH neurons are incompletely understood. Recent studies have identified multiple factors extrinsic and Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptFront Neuroendocrinol. Author manuscript; available in PMC 2012 January 1. intrinsic to GnRH neurons that control specific steps along the migratory route (discussed in (6-9)). This review updates the list of candidate proteins and pathways involved in GnRH neuronal migration and highlights...

Development of the hypothalamus: conservation, modification and innovation

“…However, as differentiating neurons move to the final location where they begin to make functional connections, some populations undergo a large tangential migration along the A/P or D/V axes (Puelles et al, 2016). An exceptional example of this process is illustrated by GnRH neurons, which originate outside the hypothalamus, migrate into the preoptic area, and send projections to the ME (Wierman et al, 2011). Through the processes of neuronal specification and migration, species-specific anatomical modules can be created that contain multiple cell types functioning together to regulate individual behaviors.…”

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