Olfactory and vomeronasal innervation of the olfactory bulbs are not essential for GnRH-1 neuronal migration to the brain

Gonadotropin releasing hormone-1 (GnRH-1) neurons migrate from the developing olfactory pit into the hypothalamus during embryonic development. Migration of the GnRH-1 neurons is required for mammalian reproduction as these cells control release of gonadotropins from the anterior pituitary gland. Disturbances in GnRH-1 cell migration, GnRH-1 synthesis, secretion or signaling lead to varying degrees of hypogonadotropic hypogonadism (HH), which impairs pubertal onset and fertility. HH associated with congenital olfactory defects is clinically defined as Kallmann Syndrome (KS). The association of olfactory defects with HH in KS suggested potential direct relationship between defective olfactory axonal routing, lack of olfactory bulbs and aberrant GnRH-1 cell migration. However, it has never been experimentally proven that the formation of axonal connections of the olfactory and vomeronasal neurons to their functional targets are necessary for the migration GnRH-1 neurons to the hypothalamus. Loss-of-function of the Arx-1 homeobox gene leads to the lack of proper formation of the olfactory bulbs with abnormal axonal termination of olfactory sensory neurons (Yoshihara et al., 2005). We exploited the Arx-1null mouse line to investigate the role of the olfactory system (olfactory/vomeronasal fibers and OBs) in controlling GnRH-1 migration to the hypothalamus. Our data proves that correct development of the OBs, and axonal connection of the olfactory and vomeronasal sensory neurons to the forebrain are not needed for GnRH-1 neuronal migration. Moreover, we prove that the terminal nerve, which forms the GnRH-1 migratory scaffold, follows different guidance cues and differs in its genetic expression from olfactory and vomeronasal sensory neurons. Significance Statement Gonadotropin Releasing Hormone-1 (GnRH-1) neurons control the reproductive axis of vertebrates. During embryonic development, these neurons migrate from the olfactory pit to the hypothalamus. GnRH-1 cell migration is commonly believed to take place along the olfactory axons. Our work reveals that correct olfactory bulb development and targeting of the olfactory and vomeronasal sensory neurons to the brain are not required for this migration. Our work challenges the idea that GnRH-1 neuronal migration to the hypothalamus relies on correct routing of the olfactory and vomeronasal sensory neurons. We provide a new basis for interpreting genetic correlations between anosmia, lack of olfactory bulbs, and hypogonadotropic hypogonadism in Kallmann Syndrome.

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