Mechanisms of GnRH Neuron Migration During Development
Gonadotropin releasing hormone (GnRH) neurons migrate from the vomeronasal organ (VNO) in the nose to the ventral forebrain. Failure to do so is associated with anosmia (inability to smell) and hypogonadism (reproductive incompetence). In mice, the migration of about 1200 GnRH neurons mostly takes place between E11 and E15, although some cells continue migrating neonatally. We have examined several factors that play key roles in the migration of these cells. In one set of experiments, we manipulated the expression of the adhesion molecule PSA-NCAM in order to evaluate its role in migration. Removal of PSA-NCAM enzymatically, in vivo, E12 mice inhibited the migration of GnRH cells significantly over a 3 day period by about 50%.
We also have examined the role of gamma amino butyric acid (GABA) in migration of these neurons. A subset of GnRH neurons also express GABA, which is thought to play a role and chemokinetic role during development in addition to its inhibitory neurotransmitter function in mature neurons. In vivo and in vitro analyses using agonists and antagonists of GABA reveal its role in migration of these cells.
We have also begun to study factors that determine the direction of migration of GnRH neurons. We had previously shown that these cells migrate in contact with a unique branch of the vomeronasal nerve (VNN) that grows into the forebrain, then turns ventrally. GnRH neurons migrate almost exclusively on this caudal branch of the VNN (cVNN). Thus, the trajectory taken by this axon branch determines the direction of migration of the neurons. We have recently shown that netrin-1/DCC interactions guide the cVNN ventrally in the forebrain. Netrin-1 is heavily expressed in the ventral forebrain and cVNN axons turn ventrally towards the netrin-1 source after crossing the cribriform plate. In DCC mutant the cVNN fails to turn ventrally and in some cases grows into the medial wall of the cerebral cortex. GnRH neurons fail to turn ventrally in DCC mutant mice and large numbers are found in the cortex as early as E13. The role of other netrin/receptor family members are under investigation.