Gonadotropin releasing-hormone (GnRH or LHRH) regulates the hypothalamo-pituitary-gonadal (HPG) axis in vertebrates. GnRH neurons that regulate the HPG axis derive from progenitor cells in the nasal compartment and migrate along vomeronasal fibers across the cribriform plate into the forebrain. GnRH neurons migrate over a long route that provides many factors for guidance. Early in their migration, GnRH neurons always follow fibers; if fiber trajectories are altered, GnRH neurons follow the altered fiber trajectories. Netrin-1 and its receptor DCC are strongly implicated in determining the path of olfactory fibers that guide GnRH neurons. Genetic deletion of ligand or receptor changes the trajectory of the fibers and GnRH neurons follow. The neurotransmitter gamma-aminobutyric acid (GABA) is associated with the GnRH migration pathway in species ranging from humans to lamprey. In mice and rats, GABA is found transiently within GnRH neurons migrating through the nasal compartment. When pregnant mice were treated with the GABA-A receptor antagonist bicuculline, GnRH neuron-fiber interactions were decreased, and GnRH neuron positions were disrupted in adulthood. When glutamic acid decarboxylase (GAD67) was transgenically placed under the control of a GnRH promoter, excess GABA was produced in GnRH neurons, and cell migration was altered. GnRH neurons found aberrant targets in dorsal regions and failed to reach normal caudal locations. Finally, we view GnRH neuron migration directly in vitro, in slices that include the nasal compartment, cribriform plate region, and basal forebrain. We find that the integrity of vomeronasal fibers at the cribriform plate is critical for the pattern of migration throughout the nasal compartment. As GnRH neuron migration proceeds they encounter more cues and must make more choices. The diversity of GnRH neuron locations is a testament to the different choices made by individual neurons. Supported by HD33441 (GAS, SAT).
22 - 24 Mar 2004
British Endocrine Societies