Ethylene Dichloride Disruption of Fertility in Male Mice

Howell

Singh

et al. 2016

Sci Rep

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.

Section: Resultsmentioning

confidence: 99%

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

Howell

Singh

et al. 2016

Sci Rep

“…3E ). We scored seminiferous tubule architecture on a previously described 1-to-10 scale in which 1 and 10 represent complete loss of cells and complete progression of spermatogenesis, respectively 33 , 36 . The average score of seminiferous tubules from C +/+ / Tia1 −/− testis was significantly reduced compared to C +/+ testis (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Photographs of sections were taken with a Nikon microscope with Spot Advanced software (Diagnostic Imaging, Inc.). Seminiferous tubules were analyzed with a previously published 10-point scoring system to assess the progression of spermatogenesis 36 . Twenty seminiferous tubules from all areas of each testis were scored.…”

Section: Methodsmentioning

confidence: 99%

TIA1 is a gender-specific disease modifier of a mild mouse model of spinal muscular atrophy

Howell

Singh

et al. 2017

Sci Rep

Spinal muscular atrophy (SMA) is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. The nearly identical SMN2 cannot compensate for SMN1 loss due to exon 7 skipping. The allele C (C +/+) mouse recapitulates a mild SMA-like phenotype and offers an ideal system to monitor the role of disease-modifying factors over a long time. T-cell-restricted intracellular antigen 1 (TIA1) regulates SMN exon 7 splicing. TIA1 is reported to be downregulated in obese patients, although it is not known if the effect is gender-specific. We show that female Tia1-knockout (Tia1 −/−) mice gain significant body weight (BW) during early postnatal development. We next examined the effect of Tia1 deletion in novel C +/+/Tia1 −/− mice. Underscoring the opposing effects of Tia1 deletion and low SMN level on BW gain, both C +/+ and C +/+/Tia1 −/− females showed similar BW gain trajectory at all time points during our study. We observed early tail necrosis in C +/+/Tia1 −/− females but not in males. We show enhanced impairment of male reproductive organ development and exacerbation of the C +/+/Tia1 −/− testis transcriptome. Our findings implicate a protein factor as a gender-specific modifier of a mild mouse model of SMA.

“…1e, right panel). We assessed the health of seminiferous tubules using an established scale (Daigle et al 2009). The average score for C/C testes indicated an overall reduction in post--meiotic cells and disrupted spermatogenesis ( Fig.…”

Section: C/c Males Exhibit Small Testes With Impaired Spermatogenesismentioning

confidence: 99%

“…We utilized a previously published 10--point scoring system to assess the progression of spermatogenesis within the seminiferous tubules (Daigle et al 2009).…”

Section: Histological Analysis Of Tissuementioning

confidence: 99%

Novel Functions of the Survival Motor Neuron Protein

There are many people that I would like to thank for their support and guidance throughout my life and graduate career. First and foremost, I would like to thank my advisor, Dr. Ravindra Singh, for guiding me through my graduate research and constantly challenging me to see beyond the day-today matters of research to the larger whole. I would like to thank all the members of the Singh lab, both past and present, who have contributed to the research contained in this text, both materially and intellectually. I would also like to thank everybody who has served on my committee, Drs. Jeffrey Beetham, Jeffrey Trimarchi, Peng Liu, Brian Lee, and Drena Dobbs, for their guidance and advice. Finally, I would like to thank my parents, Ruth and James Ottesen, for raising an inquisitive little daydreamer to become the inquisitive not-so-little daydreamer that I am today.