Effects of an Impaired Sonic Hedgehog Signaling Pathway and a Nonfunctional Gli3 Protein on GnRH-1 Neuronal Migration in Gli3Xt/Xt mutants
Gonadotropin releasing hormone (GnRH) is the master regulatory hormone for sexual development. During embryonic development, gonadotropin releasing hormone-1 neurons (GnRH-1ns) form in the olfactory pit and migrate, along axonal Peripherin positive fibers, from the nasal area to the pre-optic area of the basal forebrain. Upon migration into the brain, GnRH-1ns release GnRH. Defective migration of GnRH-1ns can result in hypogonadotropic hypogonadism (HH), a condition that results in lack of sexual development and infertility. When HH appears associated with reduced or absent sense of smell, it is clinically defined as Kallmann Syndrome (KS) (Paolo E Forni & Wray, 2015). The neurons that connect the nasal area to the basal forebrain and the molecular mechanisms that control GnRH-1 neuronal migration are still largely unknown. Sonic hedgehog (Shh) plays important roles in modulating cell motility and reactivity to chemorepellants. Gli3 is a transcriptional effector; it can act as either a transcriptional activator or repressor, mediated by the Shh signaling pathway. We found that Patched- 2, a receptor for Shh, is expressed along the GnRH-1 migratory pathway. To understand if Shh and Gli3 play a role in GnRH-1 development, we analyzed GnRH-1 migration in Gli3Xt/Xt mouse mutants. In these mutants, we observed a dramatic reduction in the number of GnRH-1ns able to migrate form the nasal area into the brain. In Gli3Xt/Xt mutants, GnRH-1ns were found proximal to the vomeronasal organ forming tangles with a subset of Peripherin positive fibers, which were found to extend as far as the forebrain junction, where they also tangle in response to the lack of olfactory bulbs. Our data suggests that the loss of function of the Gli3 gene impairs the formation of the GnRH-1 migratory scaffold and GnRH-1 migratory ability. These observations indicate that Gli3 is a candidate gene for the etiology of HH.