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Gonadotropin-releasing hormone (GnRH) neurons have a pivotal role in the physiological functions of hypotahlamic-pituitary-gonadal (HPG) axis. The pulsatile releasing of GnRH hormone into the hypophyseal portal circulation at the median eminence represent the first domino in the HPG cascade of events that regulate the development, fertility and aging in all vertebrates. These neurons principally originate in the olfactory placode and migrate during early embryonal stages into the hypothalamus. Alterations in developmental processes or in the releasing of GnRH hormone lead to a rare and complex disorder of the reproductive axis called congenital hypogonadotropic hypogonadism (CHH). Genetic screening of human patients and the use of model systems have led to the identification of several genes involved in the CHH pathogenesis underlying its oligogenic nature. Nevertheless CHH remains, for a large cohort of patients, idiopathic and GnRH neurogenesis processes not fully understood. This is due to intrinsic difficulties that exist in the analysis of earliest embryonic developmental stages and in the methodologies developed to study the CHH-causing genes. In this regard, zebrafish embryos, on account of its external fertilization and development, allow a real-time analysis that could overcome some of the above mentioned limitations. Moreover, the recent availability of several transgenic zebrafish reporter lines makes it an excellent model for the study of the oligogenic mechanisms leading to CHH.

Fertility critically depends by a small number of hypothalamic neurons secreting the neurohormone GnRH. During development GnRH neurons migrate from the nasal placode to the hypothalamus by following the migratory path formed by the vomeronasal axons. Developmental defects of this process can cause congenital GnRH deficiency (GD), characterized by absent/delayed puberty and consequent infertility. The underlying mutated loci are for the majority of GD cases unknown, partially because of a poor understanding of the molecular mechanisms that control the development of these crucial neuroendocrine cells. Here we provide evidence of the importance of class 3 semaphorins and their receptors in this process. Specifically, I will explain how two different semaphorins play distinct roles during the migration of GnRH neurons. Thus, semaphorin3A affects the migration of GnRH neurons in the nasal compartment, via the co-receptors Neuropilin-1 and 2, whereas semaphorin3E via its receptor plexind1 controls the survival of GnRH neurons once positioned in the hypothalamus. Accordingly, disrupted semaphorin signalling may be involved in the aethiopathogenesis of genetic diseases characterized by GnRH deficiency.