Defective signaling through plexin-A1 compromises the development of the peripheral olfactory system and neuroendocrine reproductive axis in mice

Abstract

The olfacto-genital syndrome (Kallmann syndrome) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. This is a genetically heterogeneous developmental disease with various modes of transmission, including oligogenic inheritance. Previous reports have involved defective cell signaling by semaphorin-3A in the disease pathogenesis. Here, we report that the embryonic phenotype of Plxna1-/- mutant mice lacking plexin-A1 (a major receptor of class 3 semaphorins), though not fully penetrant, resembles that of Kallmann syndrome fetuses. Pathohistological analysis indeed showed a strongly abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the hypothalamic brain region in some of the mutant mice, which resulted in reduced fertility in adult males. We thus screened 250 patients for the presence of mutations in PLXNA1, and identified different nonsynonymous mutations (p.V349L, p.V437L, p.R528W, p.H684Y, p.G720E, p.R740H, p.R813H, p.R840Q, p.A854T, p.R897H, p.L1464V, p.K1618T, p.C1744F), all at heterozygous state, in 15 patients. Most of these mutations are predicted to affect plexin-A1 stability or signaling activity based on predictive algorithms and a structural model of the protein. Moreover, in vitro experiments allowed us to show the existence of deleterious effects of eight mutations (including a transcript splicing defect), none of which are expected to result in a complete loss of protein synthesis, targeting, or signaling activity, though. Our findings indicate that signaling insufficiency through plexin-A1 can contribute to the pathogenesis of Kallmann syndrome, and further substantiate the oligogenic pattern of inheritance in this developmental disorder.

PLXNA1 and PLXNA3 cooperate to pattern the nasal axons that guide gonadotropin-releasing hormone neurons

“…To establish which of the four Plxna genes is expressed in a pattern consistent with a role in guiding the axons that ensure GnRH neuron migration, we performed in situ hybridisation of sections through the wild-type mouse embryo nose. Agreeing with prior reports (Marcos et al, 2017;Murakami et al, 2001;Suto et al, 2003), Plxna1 was expressed at E12.5 and E14.5 in both the VNO and OE, and Plxna3 had a similar expression pattern (Fig. S2A,B).…”

“…Accordingly, mice lacking SEMA3A signalling through NRP1 and NRP2 have similar axon and GnRH neuron defects to mice lacking SEMA3A (Cariboni et al, 2011). Mutations in NRP1, NRP2 and PLXNA1 have also been found in individuals with KS (Kotan et al, 2019;Marcos et al, 2017), although PLXNA1 loss affects the GnRH neuron and olfactory systems in mice only mildly (Marcos et al, 2017). These findings raise the possibility that PLXNA1 acts in partial redundancy with another A-type plexin.…”

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

“…the embryonic phenotype of Plxna1-/-mutant mice, which lack plexin-A1, is similar to that of human KS fetuses (161). Pathohistological analyses revealed abnormal development of the peripheral olfactory system and defective embryonic migration of GnRH neurons to the hypothalamic brain region, resulting in reduced fertility in adult males but not in females.…”

“…Pathohistological analyses revealed abnormal development of the peripheral olfactory system and defective embryonic migration of GnRH neurons to the hypothalamic brain region, resulting in reduced fertility in adult males but not in females. The same authors screened 250 patients with full KS for the presence of PLXNA1 mutations, and identified different nonsynonymous mutations in 15 patients, all in the heterozygous state (161). These rare variants were predicted in silico to affect plexin-A1 stability or signaling, and functional assays confirmed the deleterious impact of some identified variants.…”

Prevalence and associated phenotypes of PLXNA1 variants in normosmic and anosmic idiopathic hypogonadotropic hypogonadism

“…In the study with Plxna − / − mouse model, some (5/18) had a Kallmann-like phenotype, but the greater part was normosmic. 11 Therefore, the animal model of Plxna1 deficiency may fairly faithfully represent the situation in humans with PLXNA1 variants.…”