Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism

Abstract

Kallmann syndrome (KS) is a genetic disease characterized by hypogonadotropic hypogonadism and impaired sense of smell. The genetic causes underlying this syndrome are still largely unknown, but are thought to be due to a developmental defect in the migration of gonadotropin-releasing hormone (GnRH) neurons. Understanding the causes of the disease is hampered by lack of appropriate mouse models. GnRH neurons are hypothalamic cells that centrally control reproduction in mammals by secreting the GnRH decapeptide into the portal blood vessels of the pituitary to stimulate the production of gonadotropins. During development, these cells are born in the nasal placode outside the brain and migrate in association with olfactory/vomeronasal axons to reach the forebrain and position themselves in the hypothalamus. By combining the analysis of genetically altered mice with in vitro models, we demonstrate here that a secreted guidance cue of the class 3 semaphorin family, SEMA3A, is essential for the development of the GnRH neuron system: loss of SEMA3A signalling alters the targeting of vomeronasal nerves and the migration of GnRH neurons into the brain, resulting in reduced gonadal size. We found that SEMA3A signals redundantly through both its classical receptors neuropilin (NRP) 1 and, unconventionally, NRP2, while the usual NRP2 ligand SEMA3F is dispensable for this process. Strikingly, mice lacking SEMA3A or semaphorin signalling through both NRP1 and NRP2 recapitulate the anatomical features of a single case of KS analysed so far, and may therefore be used as genetic models to elucidate the pathogenesis of KS.

Neuroendocrinology

“…All but one mutation were very rare. Eight mutations were shown to be loss-of-function, which confirms the model observed in Sema-3A knockout mice [2]. However, these heterozygous mutations do not fully explain the KS phenotype.…”

Biallelic SEMA3A defects cause a novel type of syndromic short stature

“…Involvement of SEMA3A in T-cell differentiation may explain the early liability to infections in the patient [Garcia et al, 2011]. Finally, a heterozygous intragenic SEMA3A deletion was recently observed in a father and his two children with signs of Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) and supported by the mouse findings of Cariboni et al [2011] was considered causative . However, a study of SEMA3A mutations in 386 patients with Kallmann syndrome suggested that monoallelic mutations in SEMA3A were not sufficient to induce the abnormal phenotype, but may contribute to the pathogenesis of Kallmann syndrome through synergistic effects with mutant alleles of other disease-associated genes [Hanchate et al, 2012].…”

“…However, while the patient only had a minor structural heart anomaly and normal intellectual development, knock-out mice commonly die from heart failure and show abnormal neuronal architecture which was considered a correlate of lissencephaly [Behar et al, 1996] and Kallmann syndrome [Cariboni et al, 2011]. Therefore, the preserved $20% expression of an apparently grossly functioning protein in the patient may be sufficient to maintain cortex and heart function.…”

The role of the genetic factors in pathogenesis of hypogonadotropic hypogonadism

“…Гипоталамические ГнРГ-нейроны в отличие от других нейронов, высвобождающих гормоны, фор-мируются вне мозга [6]. Число нейронов, продуци-рующих ГнРГ в гипоталамусе человека, относитель-но мало (<2000).…”

“…Недостаток белка ухудшает расположение нейронов ГнРГ в гипоталамусе, что приводит к нарушению нейроэндокринного меха-низма регуляции полового развития [6].…”