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.

Diverse role of survival motor neuron protein

“…In the case of osteoarthritis, SMN is expressed at an aberrantly high level in cartilage [54]. On the other hand, low SMN expression has been recently linked to testicular defects and male infertility [57]. These results support that both aberrantly low and high SMN expression could result in pathological conditions.…”

“…Consistent with the role of SMN in DNA repair, DNA damage has been reported as one of the early symptoms in the skeletal muscles of a mouse model of SMA [225]; this finding suggests a direct involvement of SMN in DNA repair. DNA damage was also recorded as one of the characteristic features of the testicular cells in another mouse model of SMA [57]. …”

“…SMN reduction affects the development and function of the cardiovascular system [276–278], lungs [278,279], bone [280], intestine [278,281,282], liver [283,284], pancreas [285], spleen [286] and testis [57]. Although the exact mechanism by which SMN influences the development and function of these organs is a matter of future investigation, it is clear that in addition to the nervous system the effective treatments for SMA will need to address peripheral organ defects as well.…”

“…Supporting a role of SMN in mammalian testicular development and male fertility, its levels in testis are very high compared to other organs and tissues due in part to the predominant inclusion of exon 7 during SMN2 pre-mRNA splicing [55,56]. Consistently, under the condition of decreased SMN levels, male mice display defective testicular development, impaired spermatogenesis and reduced fertility [57]. Interestingly, an aberrant high SMN expression was recorded in osteoarthritis cartilage compared to the normal cartilage [54].…”

Advances in modeling and treating spinal muscular atrophy

“…Studies in an intermediate SMA mouse model uncovered progressive loss of insulin-producing β cells and an increase in glucagon-producing α cells in the pancreatic islets, as well as defects in glucose metabolism upon fasting [31], which appear to occur independent of neuromuscular pathology [32]. A reduction in testis size and spermatogenesis associated with decreased fertility has also been documented in a mild mouse model [33], indicating a requirement for SMN in postnatal development of the male reproductive organ. Lastly, the enteric nervous system controlling smooth muscle of the colon also exhibits vulnerability to SMN deficiency resulting in gastrointestinal symptoms [34•].…”