Article

MicroRNA-21 regulates the self-renewal of mouse spermatogonial stem cells

Department of Animal Biology, School of Veterinary Medicine, and Penn Bioinformatics Core, University of Pennsylvania, Philadelphia, PA 19104, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 08/2011; 108(31):12740-5. DOI: 10.1073/pnas.1109987108
Source: PubMed

ABSTRACT MicroRNAs (miRs) play a key role in the control of gene expression in a wide array of tissue systems, where their functions include the regulation of self-renewal, cellular differentiation, proliferation, and apoptosis. However, the functional importance of individual miRs in controlling spermatogonial stem cell (SSC) homeostasis has not been investigated. Using high-throughput sequencing, we profiled the expression of miRs in the Thy1(+) testis cell population, which is highly enriched for SSCs, and the Thy1(-) cell population, composed primarily of testis somatic cells. In addition, we profiled the global expression of miRs in cultured germ cells, also enriched for SSCs. Our results demonstrate that miR-21, along with miR-34c, -182, -183, and -146a, are preferentially expressed in the Thy1(+) SSC-enriched population, compared with Thy1(-) somatic cells. Importantly, we demonstrate that transient inhibition of miR-21 in SSC-enriched germ cell cultures increased the number of germ cells undergoing apoptosis and significantly reduced the number of donor-derived colonies of spermatogenesis formed from transplanted treated cells in recipient mouse testes, indicating that miR-21 is important in maintaining the SSC population. Moreover, we show that in SSC-enriched germ cell cultures, miR-21 is regulated by the transcription factor ETV5, known to be critical for SSC self-renewal.

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    • "Several studies have found that some miRNAs participate in spermatogonia self-renewal and spermatogenesis, including miR-221, miR-21, the miR-449 cluster and miR-34b/c. miR-221 plays a crucial role in maintaining the undifferentiated state of mammalian spermatogonia through repression of KIT expression [Yang et al., 2013]; miR-21 is important in maintaining the spermatogonia population and for spermatogonia self-renewal [Niu et al., 2011]. miR-34c regulates the differentiation of mouse embryonic stem cells into male germ-like cells through RARg and promotes SSC differentiation by targeting Nanos2 [Zhang et al., 2012; Yu et al., 2014]. "
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    • "For instance, miR-34C is expressed specifically in mouse pachytene spermatocytes and in round spermatids and might play a role in regulating germ cell development [25]. miR-21 is highly expressed in mouse SSC populations and is important for self-renewal or homeostasis of SSCs [26]. Although SSCs are considered to be readily reprogrammed into gPSCs, the underlying mechanisms are poorly understood. "
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    • "High-throughput sequencing identified miR-21, along with miR-34c, -182, -183, and -146a, as being preferentially expressed spermatogonial stem cell (SSC)enriched population. The transient inhibition of miR-21 in SSCenriched germ cell cultures increased the number of germ cells undergoing apoptosis and reduced the SSC potency, indicating that miR-21 is important for maintaining the SSC population (Niu et al., 2011). miR-34c is highly expressed in spermatocytes and round spermatids (Romero et al., 2011; Bouhallier et al., 2010; Liang et al., 2012). "
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