Abstract
Survival motor neuron (SMN) is ubiquitously expressed in many cell types and its encoding gene, survival motor neuron 1 gene (SMN1), is highly conserved in various species. SMN is involved in the assembly of RNA spliceosomes, which are important for pre-mRNA splicing. A severe neurogenic disease, spinal muscular atrophy (SMA), is caused by the loss or mutation of SMN1 that specifically occurred in humans. We previously reported that SMN plays roles in stem cell biology in addition to its roles in neuron development. In this study, we investigated whether SMN can improve the propagation of spermatogonia stem cells (SSCs) and facilitate the spermatogenesis process. In in vitro culture, SSCs obtained from SMA model mice showed decreased growth rate accompanied by significantly reduced expression of spermatogonia marker promyelocytic leukemia zinc finger (PLZF) compared to those from heterozygous and wild-type littermates; whereas SMN overexpressed SSCs showed enhanced cell proliferation and improved potency. In vivo, the superior ability of homing and complete performance in differentiating progeny was shown in SMN overexpressed SSCs in host seminiferous tubule of transplant experiments compared to control groups. To gain insights into the roles of SMN in clinical infertility, we derived human induced pluripotent stem cells (hiPSCs) from azoospermia patients (AZ-hiPSCs) and from healthy control (ct-hiPSCs). Despite the otherwise comparable levels of hallmark iPCS markers, lower expression level of SMN1 was found in AZ-hiPSCs compared with control hiPSCs during in vitro primordial germ cell like cells (PGCLCs) differentiation. On the other hand, overexpressing hSMN1 in AZ-hiPSCs led to increased level of pluripotent markers such as OCT4 and KLF4 during PGCLC differentiation. Our work reveal novel roles of SMN in mammalian spermatogenesis and suggest new therapeutic targets for azoospermia treatment.
Highlights
In humans, about 15% of couples suffer from infertility, with half of those caused by factors in the male [1,2]
spermatogonia stem cells (SSCs) derived from spinal muscular atrophy (SMA) pups expressed about 3% of promyelocytic leukemia zinc finger (PLZF), which was significantly lower than wildtype and heterozygous littermate controls that possessed over 4% of PLZF positive cells (Figure 1D,E)
We demonstrated that defected Survival motor neuron (SMN) results in loss of spermatogonia in in vitro culture
Summary
About 15% of couples suffer from infertility, with half of those caused by factors in the male [1,2]. The majority of male infertility is sporadic, due to unexplained abnormalities in sperm parameters, or unexplained azoospermia [3]. For non-obstructive azoospermia (NOA), which defined as no sperm in the ejaculate due to abnormal spermatogenesis, and is the most severe form of male infertility. Unlike the obstructive azoospermia (OA) patients, the etiology of NOA is either intrinsic structure failure of testis or inadequate gonadotropin production, hormone treatment could improve the testicular function and impaired semen parameters. Not all patients respond to the hormone treatment [4]. Numerous genes have proved to have a role during germ cell development in mice, their relevance to human reproduction remains to be clarifying mainly due to the limited access to human tissues and the lack of experimental tools
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
