Severe impairment of male reproductive organ development in a low SMN expressing mouse model of spinal muscular atrophy

Thumbnail Image
Date
2016-01-01
Authors
Howell, Matthew
Singh, Natalia
Seo, Joonbae
Whitley, Elizabeth
Major Professor
Advisor
Committee Member
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract

Spinal muscular atrophy (SMA) is caused by low levels of survival motor neuron (SMN), a multifunctional protein essential for higher eukaryotes. While SMN is one of the most scrutinized proteins associated with neurodegeneration, its gender-specific role in vertebrates remains unknown. We utilized a mild SMA model (C/C model) to examine the impact of low SMN on growth and development of mammalian sex organs. We show impaired testis development, degenerated seminiferous tubules, reduced sperm count and low fertility in C/C males, but no overt sex organ phenotype in C/C females. Underscoring an increased requirement for SMN expression, wild type testis showed extremely high levels of SMN protein compared to other tissues. Our results revealed severe perturbations in pathways critical to C/C male reproductive organ development and function, including steroid biosynthesis, apoptosis, and spermatogenesis. Consistent with enhanced apoptosis in seminiferous tubules of C/C testes, we recorded a drastic increase in cells with DNA fragmentation. SMN was expressed at high levels in adult C/C testis due to an adult-specific splicing switch, but could not compensate for low levels during early testicular development. Our findings uncover novel hallmarks of SMA disease progression and link SMN to general male infertility.

Series Number
Journal Issue
Is Version Of
Versions
Series
Type
article
Comments

This article is from Scientific Reports 6 (2016): 20193, doi:10.1038/srep20193. Posted with permission.

Rights Statement
Copyright
Fri Jan 01 00:00:00 UTC 2016
Funding
DOI
Supplemental Resources
Collections