The special phenotypic characteristics of Dummerstorf superfertile mouse lines could depend on the expression levels of IGF-axis genes

To date, animal models with reproductive phenotypes are knockout or transgenic and typically exhibit reduced fertility or infertility. This limits research to studying single-gene effects or loss of fertility. By contrast, Dummerstorf high-fertility mouse lines 1 and 2 (FL1 and FL2) are two unique outbred selection models that demonstrate exceptional reproductive performance. After approximately 50 years of selection, both lines have doubled the number of ovulated oocytes per cycle and consequently their litter size (>20 vs similar to 11) compared to the unselected mice of the same founder population (Dummerstorf FZTDU, ctrl line). FL1 and FL2 exhibit atypical estrous cycle length and altered levels of hormones, such as insulin and leptin, which are associated with GnRH release and/or increased body fat content. Unlike typical cases where these factors impair fertility, they instead contribute to the FLs' high reproductive capacity: the increased ovulation rate results from an upgrade in the quality of their oocytes, influenced by different ovarian lipid profile. In the present study, we analyzed the expression of IGF-axis marker genes linked to reproductive performance and FL-specific traits in three tissues. We found that lepr, which plays a critical role in implantation, was upregulated in the FL1 uterus (1.5-fold vs. ctrl, p < 0.05). In FL1 follicles, igf1, IGF-biding proteins (IGFBP2, IGFBP4) and hsf1-which is involved in gametogenesis-were significantly upregulated (1-4-fold vs. ctrl, p < 0.05 for igf1, hsf1 and IGFBP4; p < 0.01 for igfbp2). In FL2, uterine size was reduced relatively to the body weight (similar to 0.2 % FL2 vs. 0.25 % in ctrl and 0.28 % in FL1, p < 0.001), indicating that uterus dimensions do not drive their increased litter size. These findings provide new insights into the molecular basis of high fertility and could serve as a foundation for further studies on genotype-phenotype relationships in reproductive biology.