Evidence of Fluctuating Integrated Stress Response Activity in Murine Primordial Ovarian Follicles

Abstract We are evaluating the action of the Integrated Stress Response (ISR) pathway and how its enforcement of cell cycle arrest and enhancement of a cytoprotective state contribute to the rate of primordial follicle (PF) loss. Physiological stress and damage are variable locally/regionally within the ovary, thus we predict that ISR activity within PFs will be locations-dependent. We therefore tested whether levels of the marker of the active ISR, serine 51-phosphorylation of eukaryotic Initiation Factor 2 alpha subunit (P-eIF2α), differed between oocytes and pregranulosa cells within PFs, between PFs in the same ovary, and between PFs in ovaries collected from different animals. Quantitative fluorescence analysis revealed that P-eIF2α levels correspond tightly between oocytes and pregranulosa cells within the same PFs, but that different follicles in the same ovary have varied levels of the ISR activity marker; this was consistent between animal replicates. The variation of ISR activity in PFs may therefore directly reflect local/regional differences in physiological factors that induce cell damage and stress. This feature of the dynamically changing intra-ovarian environment may influence the likelihood that PFs stay dormant or begin to grow.