PRMT5 regulates ovarian follicle development by facilitating <i>Wt1</i> translation.

Abstract

Protein arginine methyltransferase 5 (<i>Prmt5</i>) 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 <i>Prmt5</i> in granulosa cells resulted in aberrant follicle development and female infertility. In <i>Prmt5-</i>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 <i>Wt1</i> expression was regulated by PRMT5 at the protein level. PRMT5 facilitated IRES-dependent translation of <i>Wt1</i> mRNA by methylating HnRNPA1. Moreover, the upregulation of steroidogenic genes in <i>Prmt5</i>-deficient granulosa cells was repressed by <i>Wt1</i> overexpression. These results demonstrate that PRMT5 participates in granulosa cell lineage maintenance by inducing <i>Wt1</i> expression. Our study uncovers a new role of post-translational arginine methylation in granulosa cell differentiation and follicle development.