Gonadotropin-releasing hormone secreting neurons: identification of new molecules involved in their development and disease

Gonadotropin-releasing hormone (GnRH) neurons comprise a small group of cells scattered in the hypothalamus of the brain and have an important role in reproduction in mammals. During development, GnRH neurons are born in the nasal cavity and migrate into the brain in association with olfactory nerves. Defects in the migration of these neurons in humans result in infertility. This is the case in Kallmann's Syndrome, where migration of GnRH neurons and growth of olfactory axons are arrested, causing hypogonadotropic hypogonadism and anosmia. We propose here multidisciplinary experiments with the aim to elucidate some of the molecular mechanisms that guide GnRH neurons through their migratory journey. We shall also search for new genes involved in the origin, migration and differentiation of GnRH neurons. Studies of the molecular mechanisms involved in the development of these neuroendocrine cells will enhance our understanding of the aetiologies of isolated hypogonadotropic hypogonadisms in humans.

Gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus play an important role in reproductive function in mammals. These cells originate in the nasal compartment and migrate into the basal forebrainin in association with olfactory/vomeronasal nerves in embryonic life in rodents. The mechanisms underlying the establishment of the migration route and the movement of the GnRH neurons are not fully understood. We have recently investigated the brains of Neuropilin-2 knock-out mice because these animals display defasciculation of olfactory nerves and reduced fertility. We found a direct role for Neuropilin-2 and its ligands on the migration of GnRH neurons. Specifically, we found that newborn knock-out mice contained significantly fewer GnRH neurons in the hypothalamus and abnormal excess of these cells in the nose, indicating a defect in their migration at this level. Here, we propose three lines of investigation that continue to focus on the cell and molecular mechanisms that underlie each step of the long and tortuous journey of these neuroendocrine cells. Firstly, we propose to study the role of Neuropilin-1 in GnRH neuron migration and of the relative importance of the neuropilin ligands, semaphorins and VEGF, in this process. Further, we intend to establish whether the effects of neuropilin ligands are direct, as VEGF may also have indirect effects by acting on blood vessels. Secondly, we propose to study the interactions between the vascular system and GnRH neurons. Thirdly, we propose to search for new genes involved in the migration/development of GnRH neurons. The significance of the research programme lies with the opportunity to understand the mechanisms involved in the migration of GnRH neurons and to shed light into the aetiologies of monogenic disorders leading to isolated hypogonadotropic hypogonadism in humans.