Semaphorin signalling in GnRH neurons: from development to disease

In mammals, fertility critically depends on the pulsatile secretion of gonadotropin-releasing hormone (GnRH) by scattered hypothalamic neurons (GnRH neurons). During development, GnRH neurons originate in the nasal placode and migrate first in the nasal compartment and then through the nasal/forebrain junction, before reaching their final positions in the hypothalamus. This neurodevelopmental process, which has been extensively studied in mouse models, is regulated by a plethora of factors that might control GnRH neuron migration or survival as well as the fasciculation/targeting of the olfactory/vomeronasal axons along which the GnRH neurons migrate. Defects in GnRH neuron development or release can lead to Isolated GnRH Deficiency (IGD), whose underlying genetic causes are still partially unknown. Recently, semaphorins and their receptors neuropilins and plexins, a large family of molecules implicated in neuronal developmental and plasticity processes, are emerging as key regulators of GnRH neuron biology and deficiency. Specifically, semaphorins have been shown to play different roles in GnRH neuron biology, by regulating migration and survival during embryonic development as well as secretion in adulthood.