State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Fangfang Dong
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen, China
Zhiming Shen
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Haowei Wu
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Changhuo Cen
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Xiuhong Cui
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
Shilai Bao
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Protein arginine methyltransferase 5 (Prmt5) is the major type II enzyme responsible for symmetric dimethylation of arginine. Here, we found that PRMT5 was expressed at high level in ovarian granulosa cells of growing follicles. Inactivation of Prmt5 in granulosa cells resulted in aberrant follicle development and female infertility. In Prmt5-knockout mice, follicle development was arrested with disorganized granulosa cells in which WT1 expression was dramatically reduced and the expression of steroidogenesis-related genes was significantly increased. The premature differentiated granulosa cells were detached from oocytes and follicle structure was disrupted. Mechanism studies revealed that Wt1 expression was regulated by PRMT5 at the protein level. PRMT5 facilitated IRES-dependent translation of Wt1 mRNA by methylating HnRNPA1. Moreover, the upregulation of steroidogenic genes in Prmt5-deficient granulosa cells was repressed by Wt1 overexpression. These results demonstrate that PRMT5 participates in granulosa cell lineage maintenance by inducing Wt1 expression. Our study uncovers a new role of post-translational arginine methylation in granulosa cell differentiation and follicle development.
