Neurofibromin haploinsufficiency results in altered spermatogenesis in a mouse model of neurofibromatosis type 1.

Harleen Chohan,Catherine D Van Raamsdonk,Kimberly A Jett,Cornelis Van Breemen,Darian Arman,Mitra Esfandiarei,Jan M Friedman

doi:10.1371/journal.pone.0208835

Harleen Chohan, Catherine D Van Raamsdonk + Show 5 more

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https://doi.org/10.1371/journal.pone.0208835

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Abstract

The fertility of men with neurofibromatosis 1 (NF1) is reduced. Despite this observation, gonadal function has not been examined in patients with NF1. In order to assess the role of reduced neurofibromin in the testes, we examined testicular morphology and function in an Nf1+/- mouse model. We found that although Nf1+/- male mice are able to reproduce, they have significantly fewer pups per litter than Nf1+/+ control males. Reduced fertility in Nf1+/- male mice is associated with disorganization of the seminiferous epithelium, with exfoliation of germ cells and immature spermatids into the tubule lumen. Morphometric analysis shows that these alterations are associated with decreased Leydig cell numbers and increased spermatid cell numbers. We hypothesized that hyper-activation of Ras in Nf1+/- males affects ectoplasmic specialization, a Sertoli-spermatid adherens junction involved in spermiation. Consistent with this idea, we found increased expression of phosphorylated ERK, a downstream effector of Ras that has been shown to alter ectoplasmic specialization, in Nf1+/- males in comparison to control Nf1+/+ littermates. These data demonstrate that neurofibromin haploinsufficiency impairs spermatogenesis and fertility in a mouse model of NF1.

Highlights

Neurofibromatosis 1 (NF1) is a multisystem autosomal dominant condition that affects 1 in 3000 individuals
To assess the fertility of Nf1+/- male mice, we determined the number of pups produced when Nf1+/- males were crossed to Nf1+/+ control females, and Nf1+/+ control males were crossed to Nf1+/- females
We saw no evidence of post-natal death or other indications that Nf1+/- males were more aggressive with pups than Nf1+/+ control males

Summary

Introduction

Neurofibromatosis 1 (NF1) is a multisystem autosomal dominant condition that affects 1 in 3000 individuals. It is caused by germ-line mutations in the neurofibromin (NF1) gene, which is located on chromosome 17. Individuals with NF1 have fewer children, on average, than individuals in the general population, and this reduction in fertility is greater in males than females [2,3,4,5,6]. This reduction in reproductive fitness has been attributed to social rather than biological.

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