Rapid ovarian transcript changes during the onset of premature ovarian insufficiency in a mouse model

Abstract

Premature ovarian insufficiency (POI) affects 1-3% of women under 40 years of age. The identified causes are highly heterogeneous, and 70% of the cases are idiopathic. The ovarian manifestation varies from a variable population of follicles that fail to develop (follicular POI) to the absence of follicles (afollicular POI) with a transition from one to the other over time. Previously, we have described a mouse model of POI that results from an oocyte-specific deletion of N- and O-glycans; Double Mutant (DM). DM females produce only one litter before undergoing POI due to ovarian dysfunction. In this study, we have characterised the gene expression profile of prepuberal (3 weeks), fertile (6 weeks) and infertile (9 weeks) DM ovaries. Up-regulation of cathepsin K (Ctsk, with unknown ovarian function) seems to trigger transcriptional changes in DM ovaries. Significant transcriptional changes then occur rapidly, associated with morphophysiological changes displayed by DM mice throughout the onset of POI. We identified genetic pathways such as extracellular matrix and immune response as candidates for the onset of POI in DM females. Remarkably, DM mice and POI women share a set of differentially expressed genes, including a functionally and co-expressed network of Mcm (minichromosome maintenance proteins) family members. The transcriptomic profile of the DM mouse model provides novel insight into the aetiology of POI. Lay summary Problems in ovary function lead to reduced fertility or infertility. One such condition is premature ovarian insufficiency (POI) which affects 1% of women under 40 years of age, and in over 70% of these, the cause of POI is unknown. To investigate POI, we have developed a mouse model. These mice are initially fertile but develop POI by 3 months of age. In this study, we investigated the changes in genes activated in the ovaries during the transition from fertility to POI, and we did this by comparing them to normal mice; gene activation leads to molecule production. A molecule known as cathepsin K seems to trigger changes during the onset of POI, followed by others related to structure and immune response pathways. In addition, some genes were identified that are similar between the POI mice and POI women.