The expression of Y-linked Zfy2 in XY mouse oocytes leads to frequent meiosis 2 defects, a high incidence of subsequent early cleavage stage arrest and infertility

Abstract

Outbred XYSry- female mice that lack Sry due to the 11 kb deletion Srydl1Rlb have very limited fertility. However, five lines of outbred XYd females with Y chromosome deletions YDel(Y)1Ct-YDel(Y)5Ct that deplete the Rbmy gene cluster and repress Sry transcription were found to be of good fertility. Here we tested our expectation that the difference in fertility between XO, XYd-1 and XYSry- females would be reflected in different degrees of oocyte depletion, but this was not the case. Transgenic addition of Yp genes to XO females implicated Zfy2 as being responsible for the deleterious Y chromosomal effect on fertility. Zfy2 transcript levels were reduced in ovaries of XYd-1 compared with XYSry- females in keeping with their differing fertility. In seeking the biological basis of the impaired fertility we found that XYSry-, XYd-1 and XO,Zfy2 females produce equivalent numbers of 2-cell embryos. However, in XYSry- and XO,Zfy2 females the majority of embryos arrested with 2-4 cells and almost no blastocysts were produced; by contrast, XYd-1 females produced substantially more blastocysts but fewer than XO controls. As previously documented for C57BL/6 inbred XY females, outbred XYSry- and XO,Zfy2 females showed frequent failure of the second meiotic division, although this did not prevent the first cleavage. Oocyte transcriptome analysis revealed major transcriptional changes resulting from the Zfy2 transgene addition. We conclude that Zfy2-induced transcriptional changes in oocytes are sufficient to explain the more severe fertility impairment of XY as compared with XO females.

Genomes of Ellobius species provide insight into the evolutionary dynamics of mammalian sex chromosomes

“…Such XY females would be expected to have very limited fertility, based on what is known from studies on the deleterious effect of expression of Y-linked genes in oocytes on meiosis and early embryonic development, in XY Sry -female mice (Vernet et al 2014b). Also in X * Y female wood lemmings (more closely related to the Ellobius genus), whereby a modified X * dominantly induces female differentiation, the oocytes are almost invariably X * X * due to a double nondisjunction event in oocyte precursors Winking et al 1981).…”

A primer on the use of mouse models for identifying direct sex chromosome effects that cause sex differences in non-gonadal tissues

“…XYF on a B6 background are almost always sterile (PSB unpublished data), although on the MF1 outbred background, they do breed [54, 55]. Using the MF1 strain, it has been shown that it is a combination of a markedly reduced oocyte pool together with the expression of the Y-encoded transcription factor ZFY2 in the oocytes leading to impaired development of embryos prior to implantation, which severely limits the fertility [55].…”

“…XYF on a B6 background are almost always sterile (PSB unpublished data), although on the MF1 outbred background, they do breed [54, 55]. Using the MF1 strain, it has been shown that it is a combination of a markedly reduced oocyte pool together with the expression of the Y-encoded transcription factor ZFY2 in the oocytes leading to impaired development of embryos prior to implantation, which severely limits the fertility [55]. Nevertheless, estrous cycle data collected in association with an FCG behavioral study [56] revealed that estrous cycles are still present in ~85–90% of MF1 XYF at 6–8 months of age (William Davies, personal communication), demonstrating that the majority of XYF ovaries are hormonally competent.…”

“…There is evidence from the study of embryos from XO females that maternal X monosomy has deleterious effects on development of preimplantation embryos [55, 77]; these effects could come into play in Cross C . See Additional file 3 for crosses E and F that avoid this potential confound.…”

Stepwise approach to oocyte depletion inSrymutated XY female mice

“…Specifically, these XY female mice exhibit an anatomically female phenotype with ovary formation; however, they are generally infertile, exhibiting extensive loss of germ cells in the ovary except in a few cases comprising hybrid strains (Kato et al, 2013;Lovell-Badge and Robertson, 1990;Mahadevaiah et al, 1993;Park and Taketo, 2003;Taketo, 2015;Vanderhyden et al, 1997;Vernet et al, 2014b;Wang et al, 2013). Overall, it is evident that XY females form well-constructed foetal gonads consisting of sites of cyst formation, pregranulosa cells, and oogonia.…”