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Declining levels of miR-382-3p at puberty trigger the onset of spermatogenesis.

ABSTRACT: A major change in the transcriptome of testicular Sertoli cells (Scs) at the onset of puberty enables them to induce robust spermatogenesis. Through comprehensive literature mining, we generated a list of genes crucial for Sc functioning and computationally predicted the microRNAs regulating them. Differential expression analysis of microRNAs in infant and pubertal rat Scs showed that miR-382-3p levels decline significantly in pubertal Scs. Interestingly, miR-382-3p was found to regulate genes like Ar and Wt1, which are crucial for functional competence of Scs. We generated a transgenic (Tg) mouse model in which pubertal decline of miR-382-3p was prevented by its overexpression in pubertal Scs. Elevated miR-382-3p restricted the functional maturation of Scs at puberty, leading to infertility. Prevention of decline in miR-382-3p expression in pubertal Scs was responsible for defective blood-testis barrier (BTB) formation, severe testicular defects, low epididymal sperm counts and loss of fertility in these mice. This provided substantial evidence that decline in levels of miR-382-3p at puberty is the essential trigger for onset of robust spermatogenesis at puberty. Hence, sustained high levels of miR-382-3p in pubertal Scs could be one of the underlying causes of idiopathic male infertility and should be considered for diagnosis and treatment of infertility.

SUBMITTER: Gupta A

PROVIDER: S-EPMC8413679 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRNA binding proteins (RBPs) have been reported to interact with RNAs to regulate gene expression. Circular RNAs (circRNAs) are a type of endogenous non-coding RNAs, which involved in the angiogenesis of tumor. The purpose of this study is to elucidate the potential roles and molecular mechanisms of MOV10 and circ-DICER1 in regulating the angiogenesis of glioma-exposed endothelial cells (GECs).MethodsThe expressions of circ-DICER1, miR-103a-3p and miR-382-5p were detected by real-time PCR. The expressions of MOV10, ZIC4, Hsp90 and PI3K/Akt were detected by real-time PCR or western blot. The binding ability of circ-SHKBP1 and miR-544a / miR-379, ZIC4 and miR-544a / miR-379 were analyzed with Dual-Luciferase Reporter System or RIP experiment. The direct effects of ZIC4 on the Hsp90? promoter were analyzed by the ChIP experiment. The cell viability, migration and tube formation in vitro were detected by CCK-8, Transwell assay and Matrigel tube formation assay. The angiogenesis in vivo was evaluated by Matrigel plug assay. Student's t-test (two tailed) was used for comparisons between two groups. One-way analysis of variance (ANOVA) was used for multi-group comparisons followed by Bonferroni post-hoc analysis.ResultsThe expressions of RNA binding proteins MOV10, circ-DICER1, ZIC4, and Hsp90? were up-regulated in GECs, while miR103a-3p/miR-382-5p were down-regulated. MOV10 binding circ-DICER1 regulated the cell viability, migration, and tube formation of GECs. And the effects of both MOV10 and circ-DICER1 silencing were better than the effects of MOV10 or circ-DICER1 alone silencing. In addition, circ-DICER1 acts as a molecular sponge to adsorb miR-103a-3p / miR-382-5p and impair the negative regulation of miR-103a-3p / miR-382-5p on ZIC4 in GECs. Furthermore, ZIC4 up-regulates the expression of its downstream target Hsp90?, and Hsp90 promotes the cell viability, migration, and tube formation of GECs by activating PI3K/Akt signaling pathway.ConclusionsMOV10 / circ-DICER1 / miR-103a-3p (miR-382-5p) / ZIC4 pathway plays a vital role in regulating the angiogenesis of glioma. Our findings not only provides novel mechanisms for the angiogenesis of glioma, but also provide potential targets for anti-angiogenesis therapies of glioma.

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Declining levels of miR-382-3p at puberty trigger the onset of spermatogenesis.

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