Abstract
Gonadotropin releasing hormone-1 (GnRH-1) neurons play a pivotal role in controlling pubertal onset and fertility once they reach their hypothalamic location. During embryonic development, GnRH-1 neurons migrate from the nasal area to the hypothalamus where they modulate gonadotropin release from the pituitary gland. Defective migration of the GnRH-1 neurons to the brain, lack of GnRH-1 secretion or signaling cause hypogonadotropic hypogonadism (HH), a pathology characterized by delayed or absence of puberty. Binding of the guidance cue Slit2 to the receptor roundabout 3 (Robo3) has been proposed to modulate GnRH-1 cell motility and basal forebrain (bFB) access during migration. However, evidence suggests that Neural EGFL Like 2 (NELL2), not Slit2, binds to Robo3. To resolve this discrepancy, we analyzed GnRH-1 neuronal migration in NELL2, Robo3, and Slit2 knock-out mouse lines. Our data do not confirm a negative effect for monogenic Robo3 and Slit2 mutations on GnRH-1 neuronal migration from the nasal area to the brain. Moreover, we found no changes in GnRH-1 neuronal migration in the brain after NELL2 loss-of-function. However, we found that Slit2 loss-of-function alters the patterning of GnRH-1 cells in the brain, suggesting that Slit2 loss-of-function affects GnRH-1 cell positioning in the brain in a Robo3 independent fashion. Our results challenge previous theories on GnRH-1 neuronal migration mechanisms and provide a new impetus to identify and understand the complex genetic mechanisms causing disorders like Kallmann syndrome (KS) and HH.
Highlights
Precise control of neural migration and circuit formation is essential to coordinate animal behavior and neuroendocrine functions
When GnRH-1ns migrate from the nasal area to the hypothalamus at E14.5, we found Neural EGFL Like 2 (NELL2) expression in the cortex and along the GnRH-1ns migratory track, in the olfactory ensheathing cells (OECs), olfactory bulb (OB), ventral anterior olfactory nucleus, the forebrain junction (FBJ), where the Gonadotropin releasing hormone-1 (GnRH-1) neurons invade the brain, and in the preoptic area (POA; Figures 1A,B)
A previous study suggested that single mutations in roundabout 3 (Robo3) or Slit2 could severely impair GnRH-1 neuronal motility and migration to the brain (Cariboni et al, 2012)
Summary
Precise control of neural migration and circuit formation is essential to coordinate animal behavior and neuroendocrine functions. Pubertal onset and fertility requires correct development of gonadotropin releasing hormone-1 neurons (GnRH-1ns). These neurons migrate from the nasal area to the brain (SchwanzelFukuda and Pfaff, 1989). Once GnRH-1ns reach the hypothalamus, they secrete GnRH-1. Testing Mechanisms of GnRH-1ns Migration peptide to control the release of follicle-stimulating hormone and luteinizing hormone from the pituitary gland (Forni and Wray, 2015). Lack of GnRH-1 secretion or signaling causes hypogonadotropic hypogonadism (HH), a pathology characterized by delayed or absent pubertal onset and sterility. Kallmann syndrome (KS; Dodé and Hardelin, 2009) is a form of HH associated with defective olfactory development resulting in anosmia (partial or total inability to smell)
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