Endocrine and molecular factors of increased female reproductive performance in the Dummerstorf high-fertility mouse line FL1

Abstract

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.

Alterations in gonadotropin, apoptotic and metabolic pathways in granulosa cells warrant superior fertility of the Dummerstorf high fertility mouse line 1

“…The authors concluded that the expression of Sgk1 in GCs is induced by FSH via activators of the PKA pathway [ 31 ]. However, like previously described, FSH is significantly decreased in FL1 mice compared to ctrl mice [ 21 ]. However, FSH is not the only hormone that has the ability to regulate Sgk1 expression.…”

“…During follicular development, Timp1 expression can be regulated directly by the PKA signaling pathway or indirectly through IGF1 [ 26 ]. Strikingly, FSH levels are significantly decreased in FL1 mice [ 21 ] and also IGF1 levels are significantly lower in FL1 mice in estrus. The transcriptome analysis revealed no evidence that the receptors of FSH or IGF1 are differentially regulated in FL1 mice.…”

“…During the selection process, FL1 mice almost doubled the number of pups per litter compared to the unselected control line (ctrl) with no signs of growth retardation in the offspring [ 17 – 19 ]. FL1 mice ovulate approximately twice as many oocytes compared to ctrl mice [ 20 , 21 ]. Although the assumption that FL1 mice increased their ovulation rate due to higher FSH levels might be argumentative at first glance, the opposite is the case.…”

“…Although the assumption that FL1 mice increased their ovulation rate due to higher FSH levels might be argumentative at first glance, the opposite is the case. Surprisingly, FSH levels in FL1 mice are decreased by 50% compared to ctrl mice [ 21 ]. Consequently, we have to reconsider the role of high FSH levels.…”

“…Previous data of our laboratory indicate that the follicular development is improved in FL1 mice [ 21 ]. However, the cellular mechanisms leading to such increased ovulation rates despite decreased FSH levels remain mainly unclear.…”