Minireview: Recent Progress in Gonadotropin-Releasing Hormone Neuronal Migration

Abstract

Neurons that synthesize GnRH are critical brain regulators of the reproductive axis, yet they originate outside the brain and must migrate over long distances and varied environments to get to their appropriate positions during development. Many studies, past and present, are providing clues for the types of molecules encountered and movements expected along the migratory route. Recent studies provide real-time views of the behavior of GnRH neurons in the context of in vitro preparations that model those in vivo. Live images provide direct evidence of the changing behavior of GnRH neurons in their different environments, showing that GnRH neurons move with greater frequency and with more alterations in direction after they enter the brain. The heterogeneity of molecular phenotypes for GnRH neurons likely ensures that multiple external factors will be found that regulate the migration of different portions of the GnRH neuronal population at different steps along the route. Molecules distributed in gradients both in the peripheral olfactory system and basal forebrain may be particularly influential in directing the appropriate movement of GnRH neurons along their arduous migration. Molecules that mediate the adhesion of GnRH neurons to changing surfaces may also play critical roles. It is likely that the multiple external factors converge on selective signal transduction pathways to engage the mechanical mechanisms needed to modulate GnRH neuronal movement and ultimately migration.

Netrin 1 provides a chemoattractive cue for the ventral migration of GnRH neurons in the chick forebrain

“…Previous studies have already described the axophilic migration of GnRH neurons in the forebrain (Yoshida et al, 1995;Murakami et al, 2000). In mice, peripherin-positive fibers belonging to the caudal branch of the vomeronasal nerve (cVNN) are shown to take a characteristic turn ventrally into the basal forebrain, suggesting the migration of GnRH neuron to be axophilic in nature (Tobet and Schwarting, 2006). In the present study we identified another mode of migration at the most caudal level of the axophilic migratory pathway.…”

Anatomical location of mature GnRH neurons corresponds with their birthdate in the developing mouse

“…Although the mechanisms regulating the initial stages of GnRH neuron migration out of the nasal compartment and into the basal forebrain are becoming clear (for reviews, see Wray, 2002;Tobet and Schwarting, 2006;Cariboni et al, 2007), there is little information regarding the mechanisms that regulate cessation of migration, or positioning of cells within the basal forebrain.…”

“…GnRH gene expression commences at E11.5 (Schwanzel-Fukuda and Pfaff, 1989), and so serves as a reliable marker for monitoring GnRH neurons from early differentiation to adulthood. Time series in situ hybridization and immunohistochemistry experiments examining GnRH gene or protein expression, respectively, have been performed to monitor the progress of GnRH neuron migration out of the nasal region and into the brain, and, coupled with analysis of migration defect mutants, a clear picture of this process is now forming (for reviews, see Wray, 2002;Tobet and Schwarting, 2006;Cariboni et al, 2007). Despite extensive investigation into understanding the cellular and molecular underpinnings of GnRH neuron migration, particularly at the early stages, the relationship between time of differentiation and the final anatomical position of individual GnRH neurons is not known.…”

Neuropilins and Their Ligands Are Important in the Migration of Gonadotropin-Releasing Hormone Neurons

“…The mechanisms underlying the establishment of the migration route and the movement of GnRH neurons are thought to involve different classes of molecules (for review, see Tobet and Schwarting, 2006). Candidates include semaphorins and their receptors, because of their high levels of expression in the developing olfactory system (Wray, 2001).…”