Runx3 transcription factor regulates ovarian functions and ovulation in female mice. Ojima F et al. (2016) We previously demonstrated that the Runx3 transcription factor is expressed in the hypothalami, pituitaries, and ovaries of mice, and that Runx3 knockout (Runx3(-/-)) mice are anovulatory and their uteri are atrophic. Runx3 mRNA expression was detected in the granulosa cells of ovarian follicles, and in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). In the present study, we examined the effects of Runx3 knockout on the gene expression of enzymes associated with steroidogenesis. We found decreased Cyp11a1 mRNA expression in Runx3(-/-) mouse ovaries compared with that in wild-type (wt) mouse ovaries at the age of 8 weeks. In situ hybridization analysis showed that the percentages of Cyp11a1 mRNA-expressing theca cells in follicles of Runx3(-/-) mice were decreased compared with those of wt mice. In accord with the alterations in Runx3(-/-) mouse ovaries, Kiss1 mRNA levels in ARC were increased, whereas mRNA levels of kisspeptin in AVPV were decreased, and gonadotropin-releasing hormone in the preoptic area and follicle-stimulating hormone β subunit gene were increased in Runx3(-/-) mice. Following an ovarian transplantation experiment between Runx3(-/-) mice and wt mice, corpora lutea were observed when ovaries from Runx3(-/-) mice were transplanted into wt mice, but not when those from wt mice were transplanted into Runx3(-/-) mice, suggesting that Runx3 in the hypothalamo-pituitary system may drive gonadotropin release to induce ovulation in the ovary. These findings indicate that Runx3 plays a crucial role in the hypothalamo-pituitary-gonadal axis.//////////////////
type: null mutation
fertility: infertile - non-ovarian defect
Comment: Runx3 regulates folliculogenesis and steroidogenesis in granulosa cells of immature mice. Ojima F et al. (2018) We previously demonstrated that female Runx3 knockout (Runx3-/-) mice were anovulatory and their uteri were atrophic and that Runx3 mRNA was expressed in granulosa cells. To clarify how Runx3 regulates folliculogenesis and ovulation, we examine the effects of Runx3 knockout on the gene expression of growth factors associated with folliculogenesis and enzymes associated with steroidogenesis. In Runx3-/- mouse ovaries, the numbers of primary and antral follicles were lower than those in wild-type (wt) mice at 3 weeks of age, indicating that the loss of Runx3 affects folliculogenesis. The expression of genes encoding activin and inhibin subunits (Inha, Inhba and Inhbb) was also decreased in ovaries from the Runx3-/- mice compared with that in wt mice. Moreover, the expression of the genes Cyp11a1 and Cyp19a1 encoding steroidogenic enzymes was also decreased. In cultured granulosa cells from 3-week-old mouse ovaries, Cyp19a1 mRNA levels were lower in Runx3-/- mice than those in wt mice. Follicle-stimulating hormone (FSH) treatment increased Cyp19a1 mRNA levels in both wt and Runx3-/- granulosa cells in culture but the mRNA level in Runx3-/- granulosa cells was lower than that in wt ones, indicating that granulosa cells could not fully function in the absence of Runx3. At 3 weeks of age, gonadotropin α subunit, FSHβ subunit and luteinizing hormone (LH) β subunit mRNA levels were decreased in Runx3-/- mice. These findings suggest that Runx3 plays a key role in female reproduction by regulating folliculogenesis and steroidogenesis in granulosa cells.//////////////////Loss of Runx3 affects ovulation and estrogen-induced endometrial cell proliferation in female mice. Sakuma A et al. Runx3 is a transcription factor that belongs to the Runx family. We studied the function of Runx3 in the mouse ovary and uterus using the Runx3 knockout (Runx3(-/-)) mouse. Ovaries were collected from 8-week-old wild type (wt) and Runx3(-/-) mice. Histological studies showed that follicles were present at various developmental stages in the Runx3(-/-) and wt mouse ovaries. The numbers of primary, preantral and antral follicles in the Runx3(-/-) mice were significantly less than those in the wt mice while the number of primordial follicles in the Runx3(-/-) mice was not significantly different from that in the wt mice. Corpora lutea were not detected in the Runx3(-/-) mouse ovary. Gonadotropin treatment in immature female mice induced ovulation in Runx3(-/-) mice as well as in wt mice, indicating that ovaries of Runx3(-/-) mice respond to gonadotropin treatment as those in wt mouse ovaries. This suggests that failure of ovulation is due to dysfunction of regulatory mechanism of gonadotropin secretion. In addition, the uteri of Runx3(-/-) mice were atrophic, showed thin epithelial layers compared with those of the wt mice, and did not respond to estrogen in terms of DNA replication in endometrial epithelial cells. These results suggest that Runx3 takes part in the regulation of reproductive functions. Mol. Reprod. Dev. (c) 2008 Wiley-Liss, Inc.