miR-135a Suppresses Granulosa Cell Growth by Targeting <i>Tgfbr1</i> and <i>Ccnd2</i> during Folliculogenesis in Mice
Lei Wang,
Yaru Chen,
Shang Wu,
Jinhua Tang,
Gaogui Chen,
Fenge Li
Affiliations
Lei Wang
Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs & Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
Yaru Chen
Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs & Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
Shang Wu
Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs & Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
Jinhua Tang
Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs & Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
Gaogui Chen
Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs & Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
Fenge Li
Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs & Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
The success of female reproduction relies on high quality oocytes, which is determined by well-organized cooperation between granulosa cells (GCs) and oocytes during folliculogenesis. GC growth plays a crucial role in maintaining follicle development. Herein, miR-135a was identified as a differentially expressed microRNA in pre-ovulatory ovarian follicles between Large White and Chinese Taihu sows detected by Solexa deep sequencing. We found that miR-135a could significantly facilitate the accumulation of cells arrested at the G1/S phase boundary and increase apoptosis. Mechanically, miR-135a suppressed transforming growth factor, beta receptor I (Tgfbr1) and cyclin D2 (Ccnd2) expression by targeting their 3′UTR in GCs. Furthermore, subcellular localization analysis and a chromatin immunoprecipitation-quantitative real-time PCR (ChIP-qPCR) assay demonstrated that the TGFBR1-SMAD3 pathway could enhance Ccnd2 promoter activity and thus upregulate Ccnd2 expression. Finally, estrogen receptor 2 (ESR2) functioned as a transcription factor by directly binding to the miR-135a promoter region and decreasing the transcriptional activity of miR-135a. Taken together, our study reveals a pro-survival mechanism of ESR2/miR-135a/Tgfbr1/Ccnd2 axis for GC growth, and also provides a novel target for the improvement of female fertility.
