Dampened HPG axis activity and altered ovarian gene transcription in Dummerstorf high-fertility mouse line FL2

Animal models of enhanced fertility are rare, as most genetically modified mouse models with reproductive phenotype display subfertility or infertility. Here we describe the ovarian phenotype of the Dummerstorf line 2 (FL2) mouse strain, which exhibits high fertility and has been selectively bred for increased fertility over more than 190 generations. This long-term selection, outbred mouse line almost doubled the litter size to 21.5 (FL2) compared to 11.3 (unselected control line, ctrl) without showing any signs of growth retardation in the offspring. Here we show that FL2 females ovulate 25.0 oocytes per cycle compared to 13.2 in ctrl. FL2 mice remain in the estrus phase for a shorter period during a 12-day observation period. Follicle-stimulating hormone (FSH) levels are decreased, both in estrus and diestrus, compared to ctrl, whereas Luteinizing hormone (LH) levels are unaffected. The mRNA expression levels in the pituitary gland correspond to the gonadotropin levels in the blood. Progesterone levels are decreased in estrus in FL2. Hypothalamic expression levels of Gonadotropin-releasing hormone (GnRH) are decreased in diestrus. Holistic gene expression analysis indicates complex and differential regulation in estrus and diestrus in ovaries of FL2 compared to ctrl. Especially genes of the TGF-β pathway (such as Bmp3, Bmp7, Inhba) and the Wnt pathway (such as Sfrp4, Mkrn1) are differentially expressed in ovaries of FL2 females. These data indicate that reduced activity of the hypothalamic-pituitary-gonadal axis (in particular, lower levels of GnRH, FSH and progesterone), combined with altered gene transcription in the ovaries, leads to higher ovulation rates in order to achieve the breeding objective of improved fertility.