Crosstalk between PTEN/PI3K/Akt Signalling and DNA Damage in the Oocyte: Implications for Primordial Follicle Activation, Oocyte Quality and Ageing.

Mila Maidarti,Evelyn E. Telfer,Richard A. Anderson

doi:10.3390/cells9010200

Abstract

The preservation of genome integrity in the mammalian female germline from primordial follicle arrest to activation of growth to oocyte maturation is fundamental to ensure reproductive success. As oocytes are formed before birth and may remain dormant for many years, it is essential that defence mechanisms are monitored and well maintained. The phosphatase and tensin homolog of chromosome 10 (PTEN)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB, Akt) is a major signalling pathway governing primordial follicle recruitment and growth. This pathway also contributes to cell growth, survival and metabolism, and to the maintenance of genomic integrity. Accelerated primordial follicle activation through this pathway may result in a compromised DNA damage response (DDR). Additionally, the distinct DDR mechanisms in oocytes may become less efficient with ageing. This review considers DNA damage surveillance mechanisms and their links to the PTEN/PI3K/Akt signalling pathway, impacting on the DDR during growth activation of primordial follicles, and in ovarian ageing. Targeting DDR mechanisms within oocytes may be of value in developing techniques to protect ovaries against chemotherapy and in advancing clinical approaches to regulate primordial follicle activation.

Highlights

In mammalian females, oocytes are formed before birth and are surrounded by somatic cells to form structures known as follicles
The DNA of a cell is continuously threatened by various types of damage that may cause a reduction in cellular function, cell cycle progression and DNA repair [45]
We have demonstrated that dipotassium bisperoxo (5-hydroxypyridine-2-carboxyl) oxovanadate (bpv(HOpic)), a potent phosphatase and tensin homolog of chromosome 10 (PTEN)

Summary

Introduction

Oocytes are formed before birth and are surrounded by somatic cells (granulosa cells) to form structures known as follicles. The oocyte increases in size and undergoes further growth and maturation whilst still being maintained in meiotic arrest These processes are referred to as primordial follicle activation [6]. Cells 2020, 9, 200 damage accumulation [7] that may threaten genomic integrity In this context, a robust surveillance mechanism is essential to ensure that oocytes with DNA damage have it repaired or are eliminated with prevention of further growth and development [8,9], maintaining the quality of oocyte and any resulting embryo throughout the reproductive lifespan [10]. DNA damage and impaired DNA repair protein interactions in ovarian follicles activated in vitro [29] Such findings will be important in elucidating the impact of pharmacological activation of primordial follicles by manipulation of the PI3K/PTEN/Akt pathway and its impact on DDR

Methods

DNA Damage Repair Pathway within Primordial Follicles

Findings

Conclusions and Future Directions