Ovarian ageing in the Dummerstorf high fertility mouse lines – comparative analysis of outbred mouse models with different reproductive lifespan

• Applicant: Dr. Carolin Lisa Michaela Ludwig
• Subject Area: Reproductive Medicine, Urology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545922663

Female fertility decreases with advancing age. The aim of this project is to establish new mouse models for research in the field of ovarian ageing and to investigate the underlying mechanisms. The Dummerstorf high fertility mouse lines 1 (FL1) and 2 (FL2) have been selected for increased fertility for more than 200 generations. During the selection process, FL1 and FL2 females have almost doubled their litter size compared to the unselected control mouse line (ctrl). However, FL1 and FL2 females exhibit two different phenotypes of high fertility. The FL1 fertility phenotype is able to deliver high litter sizes over a long time-period. Their lifetime fecundity is in the same extend to the lifetime fecundity of ctrl females. In contrast, the FL2 fertility phenotype suffers from fertility problems in older age. The lifetime fecundity of FL2 females is significantly decreased compared to ctrl and FL1 females. Thus, the FL2 phenotype has the potential to serve as a model for increased ovarian ageing. The FL1 fertility phenotype, on the other hand, has an enormous reproductive capacity that can be maintained into older age. To detect the reasons and to understand the mechanisms leading to the two different fertility phenotypes I would like to test the following hypothesis: 1) The quantity of the non-growing primordial follicle pool is different between the two fertility phenotypes and 2) The quality of the primordial follicle pool is different between the two fertility phenotypes. The hypothesis 1) will be tested by using whole-mount immunofluorescence staining of ovaries in different developmental stages to determine the primordial reserve. To get insights into the quality of the primordial reserve a holistic gene expression approach will be performed in ovaries throughout the entire postpartum phase of primordial follicle development to gain global insights into developmental mechanisms. In addition, I aim to detect whether the age-related decline in biological and reproductive functions occurs at different rates in the two fertility phenotypes. Therefore, age-related alterations, such as functional deficits due to physiologic, morphologic and anatomic alterations, will be analyzed in the two fertility phenotypes. The comparative analysis of ctrl, FL1 and FL2 mice has the potential to deliver fundamental insights into mechanisms associated with reproductive health and lifespan. Furthermore, these worldwide unique models can provide new insights into many different aspects of female reproductive fitness and health and can improve our understanding of mechanisms associated with ovarian ageing.

• DFG Programme: Research Grants