Survival Motor Neuron Protein Participates in Mouse Germ Cell Development and Spermatogonium Maintenance

Abstract

The defective human survival motor neuron 1 (SMN1) gene leads to spinal muscular atrophy (SMA), the most common genetic cause of infant mortality. We previously reported that loss of SMN results in rapid differentiation of Drosophila germline stem cells and mouse embryonic stem cells (ESCs), indicating that SMN also plays important roles in germ cell development and stem cell biology. Here, we show that in healthy mice, SMN is highly expressed in the gonadal tissues, prepubertal spermatogonia, and adult spermatocytes, whereas low SMN expression is found in differentiated spermatid and sperm. In SMA-like mice, the growth of testis tissues is retarded, accompanied with gamete development abnormalities and loss of the spermatogonia-specific marker. Consistently, knockdown of Smn1 in spermatogonial stem cells (SSCs) leads to a compromised regeneration capacity in vitro and in vivo in transplantation experiments. In SMA-like mice, apoptosis and accumulation of the R-loop structure were significantly elevated, indicating that SMN plays a critical role in the survival of male germ cells. The present work demonstrates that SMN, in addition to its critical roles in neuronal development, participates in mouse germ cell and spermatogonium maintenance.

Effects of Survival Motor Neuron Protein on Germ Cell Development in Mouse and Human

“…After four passages, SSC derived from SMA pups expressed about 3% of PLZF, which was significantly lower than wild-type and heterozygous littermate controls that possessed over 4% of PLZF positive cells ( Figure 1 D,E). This data is consistent with our published data, which indicated that loss of SMN affects the maintenance of spermatogonia [ 19 ].…”

“…In this study, we analyzed the effect of SMN on mouse spermatogenesis and human germ cell differentiation. Using an in vitro culture assay, we found the SMN deficient SSCs were unstable during maintenance and loss of spermatogonia marker PLZF after continuous culture ( Figure 1 ), which is consistent with our previous in vivo study [ 19 ].…”

“…Previously, our group demonstrated that the deficiency of SMN results in the defects on pluripotent stem cells, affecting neurogenesis and spermatogenesis in mice [ 15 , 19 ]. Although SMN serves as a housekeeping gene in various tissues and types of cells, how SMN affects stem cells still need to be elucidated.…”

“…Recently, our group reported that the levels of survival motor neuron protein (SMN), a major assembler for the process of small nuclear ribonucleoprotein (snRNP) complex, correlate with the capacities of stem cell proliferation and differentiation in Drosophila and mice [ 15 , 16 ]. Unlike the main focus of SMN in the neuron degenerative disease, spinal muscular atrophy (SMA) [ 17 , 18 ], we found SMN is highly enriched in the mouse pluripotent ESCs, adult germ cells, and controlling the proliferation and maintenance of spermatogonia [ 15 , 19 ].…”

The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy

“…22-31 Loss of SMN1 affects all tissues, including skeletal muscle, central, peripheral and autonomic nervous system, heart, liver, lung, kidney, pancreas, spleen, ovary, and testis. 32-52 Hence, an ideal therapy for SMA must “target/remedy” the body-wide defects caused by the loss of SMN1 . The severity of SMA correlates inversely with the SMN2 copy number: the higher the copy number, the lower the severity.…”