From nose to brain: development of gonadotrophin-releasing hormone-1 neurones

Abstract

Gonadotrophin-releasing hormone-1 (GnRH-1) is essential for mammalian reproduction, controlling release of gonadotrophins from the anterior pituitary. GnRH-1 neurones migrate from the nasal placode into the forebrain during development. Although first located within the nasal placode, the embryonic origin/lineage of GnRH-1 neurones is still unclear. The migration of GnRH-1 cells is the best characterised example of neurophilic/axophilic migration, with the cells using a subset of olfactory-derived vomeronasal axons as their pathway and numerous molecules to guide their movement into the forebrain. Exciting work in this area is beginning to identify intersecting pathways that orchestrate the movement of these critical neuroendocrine cells into the central nervous system, both spatially and temporally, through a diverse and changing terrain. Once within the forebrain, little is known about how the axons target the median eminence and ultimately secrete GnRH-1 in a pulsatile fashion.

Figure 1. GnRH-1 neuroendocrine system

A. Hypothalamic-Pituitary-Gonadal axis. GnRH-1 cells send axons to the median eminence (ME) where GnRH-1 is secreted into the portal capillary system. It is via this system that GnRH-1 cells affect gonadotropes of the anterior pituitary and subsequently gonadal function. POA/AH=preoptic area/anterior hypothalamus, vmh= ventromedial hypothalamus, arc=arcuate nucleus. C and D. Photomicrographs of sections immunocyto-chemically stained for GnRH-1 at the level of the OVLT (B) and ME (C). D. Parasagittal section of a rodent brain indicating the location of GnRH-1 cells (black dots, with levels in B and C shown by lines). GnRH-1 cells are distributed in a continuum from the olfactory bulbs to the caudal hypothalamus. h=hippocampus, f=fornix, ob=olfactory bulb, mot=medial olfactory tract, ms=medial septum, db=diagonal band of Broca, mpoa=medial preoptic area, d=dorsomedial hypothalamus, ot=optic tract, v=ventromedial hypothalamus, a=arcuate nucleus, me=median eminence. E. Parasagittal section of an E14.5 mouse embryo head immunocytochemically stained for GnRH-1. GnRH-1 cells can be found migrating from the VNO through the nasal forebrain junction (NFJ) into the forebrain. Asterisk shows location of inset, III= third ventricle.

Figure 2. Development of the nasal placode/GnRH-1 neurons

Camera lucida drawing from E10.5-E12.5 mice embryos showing invagination of the nasal placode and the development of the respiratory epithelium (re), olfactory epithelium (oe) and presumptive VNO (pvno)/nasal pit (np). tv=telencephalon, III=third ventricle, IV=fourth ventricle, t=tongue, fb=forebrain. A. Parasagittal section immunocytochemically stained for Hu (early neuronal marker) shows many positive cells within the nasal placode at E10.5. B. Parasagittal section from an E11.5 GnRH-GFP mouse immunocytochemically stained for GFP shows positive cells within the presumptive VNO (pvno) C. Parasagittal section from an E12.5 mouse, immunocytochemically stained for GnRH-1 (C) shows GnRH-1 cells leaving the VNO (arrows) D. Parasagittal section from an E12.5 mouse, immunocytochemically stained for GnRH-1 (brown) and peripherin (blue) shows GnRH-1 cells associated with peripherin fibers crossing the nasal forebrain junction (NFJ), peripherin axons entering the developing olfactory bulb (OB) and GnRH-1 cells still associated with a subset of peripherin axons turning caudally towards the hypothalamus.

Figure 3. Multiple Domains Along the GnRH-1 neuronal migratory route

A. Schematic of GnRH-1 neuronal migration at E12.5-E14.5. Blue dots = GnRH-1 neurons. Np=nasal pit, oe=olfactory epithelium, ob = olfactory bulb, nfj = nasal forebrain junction. B. Schematic of axons in nasal area at E12.5-E14.5. Axons form pathways to NFJ, through the cribriform plate and predominately enter olfactory bulbs (OB), but a small subset of axons form pathway caudally on which the GnRH-1 neurons migrate (dotted line). C and D. During their movement GnRH-1 neurons are exposed to multiple regulatory domains along the migratory route (light green; nasal pit, blue; olfactory epithelium, pink; nasal mesenchyme, white; nasal forebrain junction, blue line; transient pathway, red; basal forebrain, dark green; GnRH-1 cells themselves or other migrating cells along pathway. C= parasagittal; D=coronal, nmc = nasal midline cartilage.