Shaping the Reproductive System: Role of Semaphorins in Gonadotropin-Releasing Hormone Development and Function

Giacobini, Paolo

doi:10.1159/000431021

Cited by 21 publications

(18 citation statements)

References 142 publications

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“…By performing in situ hybridization against Sema3A and Slit1 on control and Arx-1 null mice we confirmed that the forebrain is a large source of repellent molecules, which in concert, might prevent the olfactory and vomeronasal fibers, but not the TN nor the GnRH-1ns, from invading the brain (Renzi et al, 2000;Nguyen-Ba-Charvet et al, 2008). As shown previously, we observed that the Sema3 receptors, NRP1 and NRP2, are expressed by olfactory and vomeronasal neurons projecting to different regions of the MOB and AOB (Cloutier et al, 2002;Walz et al, 2002;Cloutier et al, 2004;Taku et al, 2016); however we could only detect NRP1 but not NRP2 immuno-reactivity on GnRH-1ns and TN axons Hanchate et al, 2012;Giacobini and Prevot, 2013;Giacobini, 2015). By performing in situ hybridization against Sema3A in combination with immunofluorescence for GnRH-1 and Peripherin, we observed that the TN and GnRH-1 invade the brain crossing a source of Sema3A.…”

Section: ) Led Us To Question Whether This Link Was Truly Causalsupporting

confidence: 62%

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

Taroc

Prasad

Lin

et al. 2017

Preprint

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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-1 null 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 StatementGonadotropin 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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Section: ) Led Us To Question Whether This Link Was Truly Causalsupporting

confidence: 62%

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

Taroc

Prasad

Lin

et al. 2017

Preprint

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“…By performing ISH against Sema3A and Slit1 on control and Arx-1 null mice we confirmed that the forebrain is a large source of repellent molecules, which, in concert, might prevent the olfactory and vomeronasal fibers, but not the TN nor the GnRH-1 ns, from invading the brain ( Nguyen-Ba-Charvet et al, 2008 ; Renzi et al, 2000 ). We observed that the Sema3 receptors, NRP1 and NRP2, are expressed by olfactory and vomeronasal neurons projecting to different regions of the MOB and AOB ( Cloutier et al, 2002 , 2004 ; Taku et al, 2016 ; Walz et al, 2002 ); however, we could only detect NRP1 but not NRP2 immuno-reactivity on GnRH-1 ns and TN axons ( Cariboni et al, 2011 ; Giacobini, 2015 ; Giacobini and Prevot, 2013 ; Hanchate et al, 2012 ). By performing ISH against Sema3A in combination with immunofluorescence for GnRH-1 and Peripherin, we observed that the TN and GnRH-1 invade the brain crossing a source of Sema3A.…”

Section: Discussionmentioning

confidence: 61%

The terminal nerve plays a prominent role in GnRH-1 neuronal migration independent from proper olfactory and vomeronasal connections to the olfactory bulbs

et al. 2017

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Gonadotropin-releasing hormone-1 (GnRH-1) neurons (GnRH-1 ns) 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 ns 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 a potential direct relationship between defective olfactory axonal routing, lack of olfactory bulbs (OBs) and aberrant GnRH-1 ns migration. However, it has never been experimentally proven that the formation of axonal connections of the olfactory/vomeronasal neurons to their functional targets are necessary for the migration of GnRH-1 ns to the hypothalamus. Loss-of-function of the Arx-1 homeobox gene leads to the lack of proper formation of the OBs with abnormal axonal termination of olfactory sensory neurons ( Yoshihara et al., 2005). Our data prove that correct development of the OBs and axonal connection of the olfactory/vomeronasal sensory neurons to the forebrain are not required for GnRH-1 ns migration, and suggest that the terminal nerve, which forms the GnRH-1 migratory scaffold, follows different guidance cues and differs in gene expression from olfactory/vomeronasal sensory neurons.

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“…Accordingly, defects in the organization and/or function of the GnRH system cause heterogeneous reproductive disorders that are characterized by a reduction or failure of sexual competences4344. In Sema7A ko males, a suboptimal number of GnRH neurons leads to impaired testicular growth19, which we found to be associated with lowered levels of circulating TST, reduced androgen receptor expression in the OB, and the absence of a preference/attraction towards opposite-sex smells and/or individuals that is not associated to altered olfactory perception and/or attraction to social cues.…”

Section: Discussionmentioning

confidence: 99%

Opposite-sex attraction in male mice requires testosterone-dependent regulation of adult olfactory bulb neurogenesis

Schellino

Trova

Cimino

et al. 2016

Sci Rep

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Opposite-sex attraction in most mammals depends on the fine-tuned integration of pheromonal stimuli with gonadal hormones in the brain circuits underlying sexual behaviour. Neural activity in these circuits is regulated by sensory processing in the accessory olfactory bulb (AOB), the first central station of the vomeronasal system. Recent evidence indicates adult neurogenesis in the AOB is involved in sex behaviour; however, the mechanisms underlying this function are unknown. By using Semaphorin 7A knockout (Sema7A ko) mice, which show a reduced number of gonadotropin-releasing-hormone neurons, small testicles and subfertility, and wild-type males castrated during adulthood, we demonstrate that the level of circulating testosterone regulates the sex-specific control of AOB neurogenesis and the vomeronasal system activation, which influences opposite-sex cue preference/attraction in mice. Overall, these data highlight adult neurogenesis as a hub for the integration of pheromonal and hormonal cues that control sex-specific responses in brain circuits.

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Shaping the Reproductive System: Role of Semaphorins in Gonadotropin-Releasing Hormone Development and Function

Cited by 21 publications

References 142 publications

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

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

The terminal nerve plays a prominent role in GnRH-1 neuronal migration independent from proper olfactory and vomeronasal connections to the olfactory bulbs

Opposite-sex attraction in male mice requires testosterone-dependent regulation of adult olfactory bulb neurogenesis

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