CPEB3 deficiency in mice affect ovarian follicle development and causes premature ovarian insufficiency

Fang E,Runze Zhang,He Zhang,Yuanli Liu,Tianjun Song,Chaoxia Zou,Xu Gao,Cedric Matunda,Chongyang Wang,Linlin Wang,Yanze Li,Wanli Yin,Chendan Zou,Yue Wu

doi:10.1038/s41419-021-04374-4

Abstract

Premature ovarian insufficiency (POI) is a heterogeneous and multifactorial disorder. In recent years, there has been an increasing interest in research on the pathogenesis and treatment of POI, owing to the implementation of the second-child policy in China. Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is an RNA-binding protein that can bind to specific RNA sequences. CPEB3 can bind to and affect the expression, cellular location, and stability of target RNAs. Cpeb3 is highly expressed in the ovary; however, its functions remain unknown. In this study, Cpeb3-mutant mice were used to characterize the physiological functions of CPEB3. Cpeb3-mutant female mice manifested signs of gradual loss of ovarian follicles, ovarian follicle development arrest, increased follicle atresia, and subfertility with a phenotype analogous to POI in women. Further analysis showed that granulosa cell proliferation was inhibited and apoptosis was markedly increased in Cpeb3-mutant ovaries. In addition, the expression of Gdf9, a potential target of CPEB3, was decreased in Cpeb3-mutant ovaries and oocytes. Altogether, these results reveal that CPEB3 is essential for ovarian follicle development and female fertility as it regulates the expression of Gdf9 in oocytes, disruption of which leads to impaired ovarian follicle development and POI.

Highlights

Primary ovarian insufficiency (POI) is a subclass of ovarian dysfunction in which the cause of the disease is within the ovary [1]
Cpeb3-mutant female mice display impaired fertility We previously reported that Cpeb3-mutant mice were generated by the CRISPR/Cas9 method [12] (Supplementary Fig. S1A, B, and C), followed by genotype identification through DNA sequencing and western blotting (Supplementary Fig. S1D, E)
The first set of analyses examined the impact of Cpeb3 mutation in the fertility of female mice, 3-month-old WT and Cpeb3-mutant female mice were mated with 2–3-month-old WT males with proven fecundity, for ~6 months

Summary

Introduction

Primary ovarian insufficiency (POI) is a subclass of ovarian dysfunction in which the cause of the disease is within the ovary [1]. POI is defined as a loss of ovarian function before the age of 40 and it is diagnosed by elevated serum follicle-stimulating hormone (FSH) levels (>40 IU/L), which accounts for one major cause of female infertility [2]. Multiple gene mutations can cause POI [4]. The ovarian follicle, which consists of an oocyte (egg) surrounded by one or more layers of granulosa cells, is the functional content of the ovary. Follicle development stages include the primordial follicle, primary follicle, secondary follicle, and antral follicle [5]. Abnormal development of follicles leads to subfertility and POI

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Conclusion