title: Severe impairment of male reproductive organ development in a low SMN expressing mouse model of spinal muscular atrophy.
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.
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Ottesen
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Howell
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Singh
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Joonbae
authors.initials: J
authors.lastname: Seo
authors.affiliation: Department of Veterinary Pathology, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Whitley
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Ravindra N
authors.initials: RN
authors.lastname: Singh
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007248:Infertility, Male; D008297:Male; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000150:complications* / Q000235:genetics; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D012741:Sexual Maturation / Q000235:genetics; D013091:Spermatogenesis / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism*; D013737:Testis / Q000002:abnormalities* / Q000254:growth & development* / Q000473:pathology; D059467:Transcriptome / Q000235:genetics
chemical_list: D012333:RNA, Messenger; C000597152:SMN2 protein, mouse; D055540:Survival of Motor Neuron 2 Protein
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