Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2016) 41 S17.3 | DOI: 10.1530/endoabs.41.S17.3

ECE2016 Symposia Genetics and epigenetics of testicular failure (3 abstracts)

SEMA3A and SEMA3E: from mice to Kallmann syndrome

Anna Cariboni


Italy.


Gonadotropin releasing hormone neurons are a small group of scattered hypothalamic neuroendocrine cells that control reproductive functions in all mammals and many vertebrates.

Despite their position in the adult hypothalamus, during development they originate in the nasal placode and migrate along the vomeronasal nerve to reach the forebrain and attain their final position in the hypothalamus. Failure of GnRH neurons to migrate lead to Kallmann Syndrome, a genetic disorder characterised by absent/delayed puberty and anosmia. The genes underlying KS are largely unknown but the combination of genetically modified mouse models with exome sequencing may help to identify the unknown genes.

We have previously demonstrated that class 3 semaphorin (SEMA) 3A controls the positioning of the vomeronasal nerve and therefore the migration of GnRH neurons via Neuropilin (NRP1-2) receptors (Cariboni et al. Hum Mol Gen 2011). Mice lacking SEMA3A display typical KS features including hypogonadism. Predicted by our findings on mouse models, mutations of the SEMA3A gene have been subsequently identified in patients with KS (Hanchate et al. PLOS Genet 2012).

In the search for additional SEMA3-mediated signalling pathways involved in this developmental process we found that PLEXIND1, which is the SEMA3E receptor, is expressed by GnRH neurons with a pattern of expression that is temporally complementary to NRP1. Specifically, we found that in the nasal compartment GnRH neurons express high levels of NRP1 and low levels of PLEXIND1, whereas once projecting into the forebrain they stop expressing NRP1 and express very of high levels PLXND1. Accordingly mice lacking PLXND1 show a reduction in the total number of GnRH neurons, and an increased number of caspase-positive cells in the forebrain in correspondence of GnRH neurons projecting to the medial preoptic area. This results in decreased size of their gonads and reduced fertility, both of mice lacking PlexinD1 or its SEMA3E ligand.

Predicted by our findings on mouse models, we found mutations in two siblings affected by KS in the SEMA3E gene, strongly supporting a role of SEMA3E/PlexinD1 genetic pathway in the aethiopathogenesis of KS.

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