Abstract
Sertoli cells are central and essential coordinators of spermatogenesis. Accumulating evidence has demonstrated that miRNAs participate in the regulation of Sertoli cell growth. However, the functions and the regulatory mechanisms of miRNAs in Sertoli cells of domestic animals remain largely unknown. Here we report that miR-222 overexpression repressed cell cycle progression and proliferation and promoted the apoptosis of immature porcine Sertoli cells, whereas miR-222 inhibition resulted in the opposite result. miR-222 directly targeted the 3′-UTR of the GRB10 gene and inhibited its mRNA abundance. An siRNA-induced GRB10 knockdown showed similar effects as did miR-222 overexpression on cell proliferation and apoptosis and further attenuated the role of miR-222 inhibition. Furthermore, both miR-222 overexpression and GRB10 inhibition repressed the phosphorylation of PI3K and AKT, the key elements of the PI3K/AKT signaling pathway, whereas GRB10 inhibition offsets the effects of the miR-222 knockdown. Overall, we concluded that miR-222 suppresses immature porcine Sertoli cell growth by targeting the GRB10 gene through inactivation of the PI3K/AKT signaling pathway. This study provides novel insights into the epigenetic regulation of porcine spermatogenesis by determining the fate of Sertoli cells.
Highlights
Spermatogenesis is an extraordinarily complex and tightly regulated process, which produces spermatids with the participation of multiple cell types, including macrophage, endothelial, myoid, Leydig, Sertoli, and innate lymphoid type II cells (Green et al, 2018)
We found that miR222 inhibited immature porcine Sertoli cell proliferation and promoted apoptosis. miR-222 directly targeted the 3 -untranslated region (3 -UTR) of the growth factor receptor-binding protein 10 (GRB10) gene and repressed its mRNA abundance
Knockdown of miR-222 reduced the G1 phase cell population (P < 0.05) (Figures 1A,C). These results indicated that miR-222 arrested cells in the G1 phase and further repressed cell cycle progression
Summary
Spermatogenesis is an extraordinarily complex and tightly regulated process, which produces spermatids with the participation of multiple cell types, including macrophage, endothelial, myoid, Leydig, Sertoli, and innate lymphoid type II cells (Green et al, 2018). Recent studies pointed out that non-coding RNAs [such as microRNA (miRNA)] regulate Sertoli cell proliferation (Papaioannou et al, 2009, 2011; Procopio et al, 2017). MiRNAs are a series of conserved small non-coding RNAs that are widely involved in various physiological processes, including cell proliferation, apoptosis, and differentiation, by targeting the 3 -untranslated region (3 -UTR) of mRNA and thereby causing translational inhibition or activation (Suzuki et al, 2017; Xiao et al, 2017). Regulatory roles of miRNAs in Sertoli cell proliferation, apoptosis, and synthesis functions were further proposed. MiR-202-3p induced Sertoli cell apoptosis and inhibited cell proliferation and synthesis by targeting LRP6 and Cyclin D1 of Wnt/β-catenin signaling (Yang et al, 2019). Knowledge of the functions and the regulatory mechanisms of miRNAs in Sertoli cells is still in its infancy, especially regarding porcine Sertoli cell proliferation
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