Abstract
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.
Highlights
Follicles are the basic functional units in the ovaries
To investigate the effect of PRMT5 on Wt1 Internal ribosome entry sites (IRESs) activity, granulosa cells were treated with EPZ015666 for 4 days, we found that Wt1 IRES activity was decreased 261 significantly after EPZ015666 treatment (Fig. 5D)
To further confirm the effect of 301 Heterogeneous nuclear ribonucleoprotein A1 (HnRNPA1) on Wt1 IRES activity, HnRNPA1 was overexpressed in granulosa cells, and we found that Wt1 IRES activity was significantly decreased (Fig. 6D)
Summary
Follicles are the basic functional units in the ovaries. Each follicle consists of an oocyte, the surrounding granulosa cells and theca cells in the mesenchyme. Each primordial follicle is composed of an oocyte surrounded by a single layer of flattened pregranulosa cells that remains in a dormant phase until being 51 recruited into the primary stage under the influence of two main signaling pathways(Monniaux, 2016). 57 follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are important for the growth of antral follicles, the early stages of follicle development are driven by a local oocyte-granulosa cell dialog. Abnormalities in this process may lead to follicle 60 growth arrest or atresia(Oktem & Urman, 2010; Richards & Pangas, 2010)
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