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Molecular factors of female high-fertility - a study of two outbred mouse lines selected for increased female reproductive performance

Subject Area Animal Breeding, Animal Nutrition, Animal Husbandry
Term from 2018 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 397035796
 
Final Report Year 2025

Final Report Abstract

While most reproductive models exhibit reduced fertility or infertility, the Dummerstorf high-fertility mouse lines (FL1 and FL2) offer a unique opportunity to investigate the molecular and endocrine adaptations underlying increased reproductive performance. Selected over >50 years and >200 generations FL1 and FL2 mice have nearly double the litter size of control (Ctrl) mice. Despite derived from the same fonder population (as Ctrl), FL1 and FL2 display distinct lifetime fecundity, while FL2 females showing a decrease in the number of deliveries compared to FL1 and Ctrl. Interestingly, this high-fertility phenotype does not compromise maternal health, as FL1 and FL2 dams exhibited greater resilience and lower dropout rates due to health issues than Ctrl. Endocrine profiling challenges the conventional ‘superovulation-like’ hypothesis of high fertility in FLs. Unexpectedly, FL1 mice exhibit significantly reduced FSH levels as well as decreased GnRH expression, suggesting an alternative regulatory mechanism compensating for low systemic FSH. Transcriptomic analyses of granulosa cells (GCs) and ovaries point toward enhanced follicular survival mechanisms, including reduced apoptotic signaling and possible compensating factors such as increased expression of Prl, Oxt and LH receptors, in addition to differential expression of lipid and fatty acid synthesis pathways, highlighting their role in ovarian function and follicular viability. Oocyte quality, rather than quantity, appears to be a determinant of increased ovulation rates in FLs, as has been analyzed by Brilliant Cresyl Blue (BCB) staining and morphological appearance. Hence, the number of degraded oocytes is reduced, particularly in FL1. Furthermore, superovulation experiments confirm, that stimulated FL1 and Ctrl mice ovulation rates are similar, while FL1 mice naturally ovulate more oocytes than Ctrl, reinforcing the notion of an intrinsic regulatory adaptation. Collectively, these findings suggest that nature’s selection for high fertility in FLs is not driven by a superovulation-like mechanism but rather by a complex interplay of endocrine adaptations, enhanced follicular survival, and metabolic reprogramming. This work provides new insights into the molecular and physiological determinants of fertility, offering valuable implications for reproductive biology and assisted reproductive technologies. Data generated in the project have published in eight full papers, with one additional manuscript submitted and three more in preparation. These exciting findings have also been presented and discussed at various scientific conferences. We are convinced that this work represents an important contribution to broadening our understanding of increased fertility, which may be even more important to feed the adverse effect.

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