Ablation of the MiR-17-92 MicroRNA Cluster in Germ Cells Causes Subfertility in Female Mice

Abstract

Background/Aims: Oogenesis is a highly complex process that is intricately regulated by interactions of multiple genes and signaling molecules. However, the underlying molecular mechanisms are poorly understood. There is emerging evidence that microRNAs contribute to oogenesis. Here, we aimed to investigate the role of miR-17-92 cluster in regulating oogenesis. Methods: The miR-17-92 cluster was genetically ablated in germ cells of female mice by applying the Cre-loxp system for conditional gene knockout. Mating experiment, superovulation and histological analysis were used to assess the fertility of the model female mice. TUNEL assay was used to identify apoptotic cells in ovaries. The expression level of apoptosis- and follicular atresia- related genes was evaluated by qRT-PCR. Western blotting was performed to detect protein expression. Bioinformatics software and dual luciferase reporter assay were applied to predict and verify the target of miR-17-92 cluster. Results: Deletion of miR-17-92 cluster in germ cells of female mice caused increased oocyte degradation and follicular atresia, perturbed oogenesis, and ultimately led to subfertility. Genes involved in follicular atresia and the mitochondrial apoptotic pathway were obviously up-regulated. Furthermore, we verified that miR-19a regulated oogenesis at the post-transcriptional level by targeting Bmf in the ovaries of miR-17-92 cluster conditional knockout female mice. Conclusion: The miR-17-92 cluster is an important regulator of oogenesis. These findings will assist in better understanding the etiology of disorders in oogenesis and in developing new therapeutic targets for female infertility.

miR‐17‐5p affects porcine granulosa cell growth and oestradiol synthesis by targeting E2F1 gene

“…Moreover, miR-17-92 germ cell-specific KO female mice displayed a low fecundity with increased follicular atresia and reduced ovulation rate (Wang et al, 2018). All the above indicated the potential function of miR-17-5p in folliculogenesis.…”

“…miR‐17‐5p was reported to be related to progression of ovarian cancers and endometrial cancer, and had essential roles in vital processes like cell cycle regulation, proliferation and apoptosis (Li et al, ; Shen et al, ). Moreover, miR‐17‐92 germ cell‐specific KO female mice displayed a low fecundity with increased follicular atresia and reduced ovulation rate (Wang et al, ). All the above indicated the potential function of miR‐17‐5p in folliculogenesis.…”

“…Our results showed miR‐17‐5p promoted CYP19A1 gene expression and o estrogen synthesis (Figure ). Specific knockout of the miR17‐92 gene cluster in germ cells leads to increased follicular atresia, decreased ovulation and significantly reduced fecundity in females (Wang et al, ). miR‐17‐5p is a member of the miR17‐92 gene cluster.…”

“…miR-17-5p is a member of miR-17-92 gene cluster, which encodes 6 miRNAs: miR-17, miR-18a, miR-19a, miR-20a, miR-19b and miR-92a (Mendell, 2008). KO mice that genetically ablated the miR-17-92 cluster in the germ cells of female mice displayed much-reduced fecundity with increased follicular atresia and lower ovulation numbers compared with controls (Wang, Xu, Tian, Sun, & Wu, 2018). Previous studies have shown that miR-17-5p is involved in the processes of cancer cell growth, proliferation, migration and invasion (Xiang & Wu, 2010).…”

A Preliminary Study on the Characteristics of microRNAs in Ovarian Stroma and Follicles of Chuanzhong Black Goat during Estrus

“…In addition, studies have found that the imbalance of miR-423, miR-33b, and miR-142 may lead to polycystic ovary syndrome [ 17 ]. The deletion of the miR-17-92 cluster [ 18 ] and miR-7a2 [ 19 ] can lead to infertility in female mice. This suggests that miRNA might also affect the reproductive performance of female goats, thus affecting the economic effect of the goat industry.…”