Origin and migration of luteinizing hormone-releasing hormone neurons in mammals

Luteinizing hormone-releasing hormone (LHRH) neurons are unique among hypothalamic neurons in that they originate outside of the central nervous system. In most vertebrates, LHRH-immunoreactive (-ir) neurons are detected in the epithelium of the medial olfactory pit soon after its formation. The LHRH-ir neurons migrate out of the placodal epithelium and into the brain along a migration route that consists of the central processes of the terminal, olfactory, and vomeronasal nerves. LHRH-ir cell migration follows a highly ordered course from the initial appearance of the LHRH-ir cells in the epithelium of the medial olfactory pit, to the crossing of these cells in cords on the nasal septum, to their entrance into the forebrain. Here they separate and follow an arching trajectory to their final destinations in the septal and preoptic areas and in the hypothalamus. Examination of the molecular makeup of the developing migration route reveals the presence of neural cell adhesion molecule (N-CAM) in non-LHRH-ir cells. The N-CAM-ir cells migrate into the nasal mesenchyme, trailed by N-CAM-ir axons of the olfactory, vomeronasal, and terminal nerves. These N-CAM cells and axons link the olfactory epithelia with the developing forebrain and together form scaffolding along which the LHRH-ir cells migrate into the brain. The focus of this review is on the origin and migration of LHRH-ir neurons in mammals, including humans. A discussion of Kallmann's syndrome (hypogonadotropic hypogonadism with anosmia) is included, in which there is an absence of LHRH-ir in the brain but clusters of LHRH-ir cells in the nasal cavity. This "experiment of nature" lends support to the hypothesis that all LHRH-ir cells in humans originate in the olfactory placode.