The Dummerstorf high-fertility mouse line FL1 is a worldwide unique selection experiment for increased female reproductive performance. After more than 190 generations of selection these mice doubled the amount of offspring per litter compared to the unselected control line. FL1 females have a superior lifetime fecundity and the highest Silver fecundity index that has been described in mice, while their offspring show no signs of growth retardation. The reasons for the increased reproductive performance remained unclear. Thus, this study aims to characterize the Dummerstorf high-fertility mouse line FL1 on endocrine and molecular levels on the female side. We analyzed parameters of the HPG axis on both, hormonal and transcriptional levels. GnRH and FSH concentrations were decreased in FL1 throughout the whole estrous cycle. LH was increased in FL1 mice in estrus. Progesterone concentrations were decreased in estrus in FL1 mice and not affected in diestrus. We used a holistic gene expression approach in the ovary to obtain a global picture of how the high-fertility phenotype is achieved. We found several differentially expressed genes in the ovaries of FL1 mice that are associated with different female fertility traits. Our results indicate that ovulation rates in mice can be increased despite decreased FSH levels. Cycle-related alterations of progesterone and LH levels have the potential to improve follicular maturation and interactions of endocrine and molecular factors lead to enhanced follicular survival, more successful folliculogenesis and therefore higher ovulation rates in female FL1 mice.

The development and maturation of ovarian follicles is a complex and highly regulated process, which is essential for successful ovulation. During recent decades, several mouse models provided insights into the regulation of folliculogenesis. In contrast to the commonly used transgenic or knockout mouse models, the Dummerstorf high-fertility mouse line 1 (FL1) is a worldwide unique selection experiment for increased female reproductive performance and extraordinary high fertility. Interactions of cycle-related alterations of parameters of the hypothalamic pituitary gonadal axis and molecular factors in the ovary lead to improved follicular development and therefore increased ovulation rates in FL1 mice. FL1 females almost doubled the number of ovulated oocytes compared to the unselected control mouse line. To gain insights into the cellular mechanisms leading to the high fertility phenotype we used granulosa cells isolated from antral follicles for mRNA sequencing. Based on the results of the transcriptome analysis we additionally measured hormones and growth factors associated with follicular development to complement the picture of how the signaling pathways are regulated. While IGF1 levels are decreased in FL1 mice in estrus, we found no differences in insulin, prolactin and oxytocin levels in FL1 mice compared to the control line. The results of the mRNA sequencing approach revealed that the actions of insulin, prolactin and oxytocin are restricted local to the granulosa cells, since hormonal receptor expression is differentially regulated in FL1 mice. Additionally, numerous genes, which are involved in important gonadotropin, apoptotic and metabolic signaling pathways in granulosa cells, are differentially regulated in granulosa cells of FL1 mice.We showed that an overlap of different signaling pathways reflects the crosstalk between gonadotropin and growth factor signaling pathways, follicular atresia in FL1 mice is decreased due to improved granulosa cell survival and by improving the efficiency of intracellular signaling, glucose metabolism and signal transduction, FL1 mice have several advantages in reproductive performance and therefore increased the ovulation rate. Therefore, this worldwide unique high fertility model can provide new insights into different factors leading to improved follicular development and has the potential to improve our understanding of high fertility.

Background Recently we described two outbred mouse lines which have been selected for high fertility. These mouse models doubled the number of offspring per litter. Objectives Although selected for a primarily female‐trait of high fertility (increased litter size), we were interested whether also males of the fertility lines show differences within their reproductive organs. Materials and methods We investigated males from two outbred mouse lines which have been selected for the phenotype “high fertility” for more than 170 generations. In the present study, we analysed the testicular cell type composition by flow cytometry. We further investigated the weights of reproductive organs, histomorphometry of testis as well as studied sperm motility parameters using a thermal stress assay as well as a sperm hyperactivation assay. Results Here, we describe that males of the fertility line (FL) 1 show an increased percentage of diploid cells within the testis. Flow cytometric analysis identified this enlarged cell population as Leydig cells. Testis weights were unaffected whereas the weights of seminal vesicles of FL1 and FL2 were increased compared to Ctrl bucks. FL2 males show decreased diameter of tubulus seminiferi and an enhanced spermatid/Sertoli cell index. Sperm motility parameters of FL1 and Ctrl males are initially indistinguishable but FL1 spermatozoa show a better performance in a thermal stress experiment over a 5 hours observation period. Discussion These data indicate that although selected for a primarily female‐trait of high fertility also males from the fertility lines are effected by defined alterations in their reproductive organs. Conclusion Some of these alterations are FL1‐specific others are FL2‐associated, indicating that different molecular strategies warrant the high‐fertility phenotype on the female as well as on the male side.

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