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.