miR-181b-induced SMAD7 downregulation controls granulosa cell apoptosis through TGF-β signaling by interacting with the TGFBR1 promoter.

SMAD7 disrupts the TGF-β signaling pathway by influencing TGFBR1 stability and by blocking the binding of TGFBR1 to SMAD2/3. In this study, we showed that SMAD7 attenuated the TGF-β signaling pathway in ovarian granulosa cells (GCs) by regulating TGFBR1 transcriptional activity. To function as a transcription factor, SMAD7 downregulated the mRNA levels of TGFBR1 via direct binding to the SMAD-binding elements (SBEs) within the promoter region of pig TGFBR1. We also showed that SMAD7 enhanced porcine GC apoptosis by interrupting TGFBR1 and the TGF-β signaling pathway. Interestingly, miR-181b, a microRNA that is downregulated during porcine follicular atresia, was identified to be directly targeting SMAD7 at its 3'-UTR. By inhibiting SMAD7, miR-181b could inhibit GC apoptosis by activating the TGF-β signaling pathway. Our findings provide new insights into the mechanisms underlying the regulation of the TGF-β signaling pathway by SMAD7 and miR-181b.