Inactivation of Wt1 causes pre-granulosa cell to steroidogenic cell transformation and defect of ovary development†

Dong

Shen

et al. 2021

eLife

Self Cite

Protein arginine methyltransferase 5 (Prmt5) is the major type II enzyme responsible for symmetric dimethylation of arginine. Here, we found 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 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.

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PRMT5 regulates ovarian follicle development by facilitating Wt1 translation

Dong

Shen

et al. 2021

eLife

Self Cite

“…WT1 is expressed at high levels in granulosa cells of primordial, primary, and secondary follicles but decreases with follicle development, suggesting it might be a repressor of ovarian differentiation genes in the granulosa cells 7 . Our previous study demonstrated that the Wt1 gene is required for lineage specification and maintenance of granulosa cells 8,9 . Inactivation of Wt1 causes the transformation of pregranulosa cells to steroidogenic cells.…”

Section: Discussionmentioning

confidence: 99%

“…S3). Wt1 plays a critical role in granulosa cell development, and mutation of Wt1 leads to pregranulosa cell-to-steroidogenic cell transformation 8,9 . Therefore, we further examined the expression of steroidogenic genes in Prmt5-deficient granulosa cells at P18.…”

Section: Deletion Of Prmt5 In Granulosa Cells Caused Aberrant Ovary Development and Female Infertilitymentioning

confidence: 99%

“…During follicle development, Wt1 is expressed at high levels in granulosa cells of primordial, primary and secondary follicles, but its expression is decreased in antral follicles 7 . Our previous studies demonstrated that Wt1 is required for the lineage specification and maintenance of Sertoli and granulosa cells 8,9 . However, the underlying mechanism that regulates the expression of Wt1 in granulosa cells is unknown.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PRMT5 regulates ovarian follicle development by facilitatingWt1translation

Dong

Shen

et al. 2021

Preprint

Self Cite

Protein arginine methyltransferase 5 (Prmt5) is the major type II enzyme responsible for symmetric dimethylation of arginine. Here, we found 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 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.

Whole exome sequencing identified a rare WT1 loss‐of‐function variant in a non‐syndromic POI patient

Wang

Zhang³

et al. 2021

Molec Gen & Gen Med

Background Premature ovarian insufficiency (POI) is a highly heterogeneous disease, and up to 25% of cases can be explained by genetic causes. The transcription factor WT1 has long been reported to play a crucial role in ovary function. Wt1‐mutated female mice exhibited POI‐like phenotypes. Methods and Results In this study, whole exome sequencing (WES) was applied to find the cause of POI in Han Chinese women. A nonsense variant in the WT1 gene: NM_024426.6:c.1387C>T(p.R463*) was identified in a non‐syndromic POI woman. The variant is a heterozygous de novo mutation that is very rare in the human population. The son of the patient inherited the mutation and developed Wilms’ tumor and urethral malformation at the age of 7. According to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, the novel variant is categorized as pathogenic. Western blot analysis further demonstrated that the WT1 variant could produce a truncated WT1 isoform in vitro. Conclusions A rare heterozygous nonsense WT1 mutant is associated with non‐syndromic POI and Wilms’ tumor. Our finding characterized another pathogenic WT1 variant, providing insight into genetic counseling.