Gonadotropin-releasing hormone-secreting neuron development and function: an update

The coordinated and pulsatile secretion of gonadotropin-releasing hormone (GnRH) plays a central role in vertebrate reproductive function. The development of the hypothalamo-pituitary-gonadal (HPG) axis is characterized by a complex network of molecular signals that controls, at first, migration of the GnRH neurons along the nose, through the cribriform plate, up to the frontal lobe. This migratory process is orchestrated by several factors including anosmin-1, polysialylated form of the neural cell adhesion molecule, γ-amino butyric acid, hepatocyte growth factor, chemokines, cytokines and semaphorins. Moreover, antimüllerian hormone, growth hormone and insulin-like growth factor-1 were recently reported to modulate immature GnRH neuron migration in vitro. Once arrived in the forebrain, GnRH neurons mainly localize in the medial preoptic area and their axon elongation, mediated by fibroblast growth factor receptor 1 and semaphorin 7A signaling, is essential for GnRH secretion. The physiological pulsatile release of GnRH is controlled by central and peripheral factors, including kisspeptin, neurokinin B and dynorphin from KNDy neurons, and sex steroids and leptin, respectively. GnRH pulsatile release into the hypothalamus-pituitary blood portal system stimulates luteinizing hormone and follicle-stimulating hormone secretion into the general circulation. Such knowledge also results crucial for understanding of the molecular bases of congenital and acquired dysfunction of the HPG axis, which imply severe pathological consequences, such as GnRH deficiency or congenital hypogonadotropic hypogonadism, characterized by incomplete or absent puberty and infertility.