Heterogeneity in secondary follicle development buffers the lifespan of activated oocytes to optimize female fertility in mice.

Abstract

Oocyte activation and follicular development are fundamental for fertility in mammals, yet the dynamics of activated oocytes (Act-Oos) remain unclear. Here we use a Zp3-based lineage-tracing mouse model to label Act-Oos and reconstruct their developmental trajectories and folliculogenesis across the lifespan. We uncovered age-dependent heterogeneity in Act-Oo longevity: some oocytes activated in early adulthood progressed rapidly, whereas others persisted into late or even terminal reproductive stages, supporting long-term fertility. Further analyses revealed that Act-Oo lifespan is governed by secondary follicle (SF) progression, identifying SF development as a buffering mechanism that modulates female reproductive capacity. Mechanistically, transcriptional and metabolic states vary across Act-Oos, and differential FURIN expression modulates the release of oocyte-secreted factors, coordinating Act-Oo development with that of associated SFs and thereby regulating Act-Oo lifespan. Together, these findings provide a comprehensive in vivo developmental map of Act-Oo and mouse folliculogenesis, revealing dynamic control of female reproductive capacity.