Abstract
MicroRNAs play key roles during ovary development, with emerging evidence suggesting that miR-202-5p is specifically expressed in female animal gonads. Granulosa cells (GCs) are somatic cells that are closely related to the development of female gametes in mammalian ovaries. However, the biological roles of miR-202-5p in GCs remain unknown. Here, we show that miR-202-5p is specifically expressed in GCs and accumulates in extracellular vesicles (EVs) from large growth follicles in goat ovaries. In vitro assays showed that miR-202-5p induced apoptosis and suppressed the proliferation of goat GCs. We further revealed that miR-202-5p is a functional miRNA that targets the transforming growth factor-beta type II receptor (TGFβR2). MiR-202-5p attenuated TGF-β/SMAD signaling through the degradation of TGFβR2 at both the mRNA and protein level, decreasing p-SMAD3 levels in GCs. Moreover, we verified that steroidogenic factor 1 (SF1) is a transcriptional factor that binds to the promoters of miR-202 and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) through luciferase reporter and chromatin immunoprecipitation (ChIP) assays. That contributed to positive correlation between miR-202-5p and CYP19A1 expression and estradiol (E2) release. Furthermore, SF1 repressed TGFβR2 and p-SMAD3 levels in GCs through the transactivation of miR-202-5p. Taken together, these results suggest a mechanism by which miR-202-5p regulates canonical TGF-β/SMAD signaling through targeting TGFβR2 in GCs. This provides insight into the transcriptional regulation of miR-202 and CYP19A1 during goat ovarian follicular development.
Highlights
Female fecundity is closely related to follicular development in the ovaries of mammals
To understand the mechanism(s) through which miR-202-5p is upregulated during follicular development, we focused on the transcriptional regulation and promoter regions
As steroidogenic factor 1 (SF1) enhances miR-202 expression and miR-202-5p targets TGFβR2in Granulosa cells (GCs), we investigated the mechanisms through which SF1 regulates canonical TGF-β/SMAD signaling in GCs. qPCR confirmed that SF1 overexpression decreased the mRNA expression of TGFβR2in GCs (Figure 6A)
Summary
Female fecundity is closely related to follicular development in the ovaries of mammals. Accumulating evidence suggests that the initiation of follicular atresia is mainly due to granulosa cell (GC) apoptosis (programmed cell death) [4,5]. Ovarian endocrine factors have been extensively studied in GCs apoptosis, the regulation by small noncoding RNAs (microRNAs) has attracted more attention in recent years. MicroRNAs (miRNAs) are ~22 nucleotides in length, noncoding RNAs post-transcriptionally regulate gene expression through binding to partially complementary sites on the 30 -untranslated. Dynamic changes in the levels of miRNA expression occur during ovarian development with different miRNA profiles existing [6,7]. Several miRNAs have been identified as regulators of GCs apoptosis in domestic animals, including miR-92a [8], miR-1275 [9], and let-7g [10]
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