p27kip1-dependent gene activity within pregranulosa cells implicates pathways relevant for control of primordial follicle activation in mice

The number of primordial follicles within the ovary, and their rate of activation, are critical parameters of the female reproductive lifespan. A finite number of primordial follicles are established during early ovarian development when individual oocytes are surrounded by a layer of somatic supporting pregranulosa cells. Primordial follicles remain quiescent until activated and their selective activation represents the definitive first step towards oocyte maturation and ovulation. Activation is characterised by oocyte and granulosa morphological changes. Activated granulosa cells resume proliferating, downregulating cell cycle inhibitor and transcriptional repressor Cdkn1b/p27kip1. Aside from a single wave of neonatal activation, primordial follicles activate cyclically to enter the pool of growing follicles. Mice lacking p27kip1 are infertile as all their primordial follicles activate during this neonatal wave of activation. Here, we utilise a p27kip1-null (Cdkn1b-/-) mouse line to functionally implicate a gene expression signature within the pregranulosa cells of primordial follicles undergoing activation. Using a combinatorial transcriptomic approach, we find pregranulosa cells undergoing follicle activation are characterised by the expression of several genes previously linked with mature granulosa cells as well several novel candidates: Tnni3, Slc18a2, Fam13a and Klf2. This study implicates pregranulosa cell transition as the key driver of primordial follicle activation and integrates cell-cycle regulator p27kip1 within the molecular mechanism driving pregranulosa cell transition.