GnRH, anosmia and hypogonadotropic hypogonadism--where are we?

Abstract

Gonadotropin releasing hormone (GnRH) neurons originate the nasal placode and migrate into the brain during prenatal development. Once within the brain, these cells become integral components of the hypothalamic-pituitary-gonadal axis, essential for reproductive function. Disruption of this system causes hypogonadotropic hypogonadism (HH). HH associated with anosmia is clinically defined as Kallman syndrome (KS). Recent work examining the developing nasal region has shed new light on cellular composition, cell interactions and molecular cues responsible for the development of this system in different species. This review discusses some developmental aspects, animal models and current advancements in our understanding of pathologies affecting GnRH. In addition we discuss how development of neural crest derivatives such as the glia of the olfactory system and craniofacial structures control GnRH development and reproductive function.

Keywords: Craniofacial defects; GnRH; Hypogonadotropic hypogonadism; Hypothalamic–pituitary–gonadal (HPG) axis; Kallmann syndrome; Neural crest; Olfactory ensheathing cells; Olfactory placode; Waardenburg syndrome.

Fig. 1. Hypothalamic-pituitary-gonadal (HPG) axis

GnRH-1 cells extend their axons to the median eminence where they release GnRH-1 into the portal capillary system. Gonadotrope cells of the anterior pituitary, synthesize and release gonadotropins, LH and FSH. Pituitary release of FSH and LH, control sex steroid synthesis in the gonads.

Fig.2

Schematic illustrating the different GnRH paralogs expressed by vertebrate species. * indicates hypophysiotropic form.

Fig. 3. GnRH neuronal migration in the developing nasal region in mouse

Left panels: schematics of E11.5 and E12.5 mouse sections showing developmental changes in the nasal placode (red). Nose is toward the left. Right panels – corresponding stage immunocytochemically stained for GnRH (blue, arrowheads) and peripherin (sensory axon marker, brown). GnRH neurons are apposed to axons as they migrate from the VNO to the brain. OE=olfactory epithelium, RE = respiratory epithelium, VNO= vomeronasal organ, III= 3^rd ventricle, FB = forebrain. NA=nasal area.

Fig.4. Cartoons summarizing key developmental studies (see references in figure) indicating the origin of GnRH neurons from the olfactory pit (A, B) and embryonic (C,D) and genetic (E, F) lineage of the progenitors

Though studies have been performed on different animal models the shape of the olfactory pit was adapted to the one of the mouse.

Fig.5. Fgf8 affects craniofacial growth and craniofacial signals

A) (E11.5) Whole head of Fgf8Lacz knock-in mouse showing Fgf8 (blue) is expressed in the rostral portion of olfactory pits (OP); MP-maxillary process. M=Medial; L= Lateral. B,C Coronal and parasagittal sections of E11.5 mouse nasal sections reveal that Fgf8 expression is limited to the non neurogenic portions of the olfactory pit, putative respiratory epithelium (RE), negative for the neuronal marker HuC/D (brown). R=rostral; D=dorsal; C=caudal; V=ventral. D-F) BMP4, NOG and neurogenesis. BMP4 (gray) represses neuronal cell fate acquisition leading surface ectodermal cells to acquire epidermal fate. BMP4 directly induces Nog expression (pink). Nog, by blocking BMP4, defines neurogenic permissive areas (green). Schematic, frontal view, mouse nasal area at E10.5 (based on [78; 99]) in control (E) and Fgf8 hypomorph (F). Mesenchymal BMP4 (gray) induces Nog expression (pink) in the medial and lateral mesenchyme. These sources of Nog define neurogenic areas (green) of the olfactory pit (OP). The GnRH neurons niche (light green) is defined by ventral mesenchymal sources of Nog. In response to reduced Fgf8 gene expression (F), facial BMP4 expression expanded, causing changes in Nog gene expression pattern and the neurogenic permissive areas of the olfactory pit (compare green areas and dotted line in E and F). The GnRH neurogenic niche is lost in FgF8 mutants as Nog moves from the ventral position of the pit.

Fig. 6. What happens in KS?

Schematic of mouse embryo: (A) normal projections of olfactory, vomeronasal/terminal fibers (light blue) from the olfactory epithelium (OE) and VNO to the olfactory bulb (OB); GnRH neurons (green) migrating along the putative terminal nerve (TN) to the preoptic area of the hypothalamus (POA). B,C Two different KS developmental scenarios. B) Mouse models with defective olfactory pit formation or olfactory, vomeronasal and/or GnRH-1 neuronal onset. C) Mouse models carrying mutations that affect olfactory/terminal nerve growth or path finding. Defects in OB formation can be secondary to defective neuronal projection to the brain or directly affect the ability of the olfactory fibers to connect to the brain. These cartoons summarize mouse models that recapitulate KS phenotypes linked to mutations on the listed genes.

Fig. 7. The olfactory system is composed of placodal and neural crest cells. The OECs are important players in GnRH migration

A) Section of mouse embryo E11.5 immunostained against HuCD (green, neurons) and Sox10 (Red, olfactory ensheathing cells (OECS)). Over development, the migratory mass (MM) composed of neurons and glia moves away from the olfactory (OE)/vomeronasal epithelia (VNO) toward the brain. B) Crect/RosaYFP genetic lineage tracing reveals placodal derivatives as positive for YFP expression (green). The OECs of the migratory mass are not derived from placodal progenitors. C and D) Diagrams (based on [150; 175]) representing normal GnRH neurons migrating along the olfactory/terminal nerve fibers from the nose to the brain in control animals; (C) In Sox10^null mice, where the OECs do not complete maturation (pink dots), fewer GnRH neurons migrate into the brain and olfactory sensory axons misroute/defasisculate (D). Olfactory, vomeronasal and terminal fibers (blue), GnRH neurons green, OECs red in control, pink OECs precursors in Sox10^null mutant. E) BLBP is expressed by the OECS; X-Gal staining (blue) on a section from BLBPCreIRESLacZ, [207], embryo, E12.5 immunostained for GnRH-1 (brown). GnRH-1 neurons migrate (brown) in close contact to maturing OECs (blue nuclei) (see insert). F) Model based on [127] representing OECS releasing molecules important for GnRH neuronal migration/motility on olfactory/terminal fibers.