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Sex reversal can occur in XY humans with only a single functional  WT1  or  SF1  allele or a duplication of the chromosome region containing  WNT4 . In contrast, XY mice with only a single functional  Wt1 ,  Sf1 , or  Wnt4  allele, or mice that over-express  Wnt4  from a transgene, reportedly are not sex-reversed. Because genetic background plays a critical role in testis differentiation, particularly in C57BL/6J (B6) mice, we tested the hypothesis that  Wt1 ,  Sf1 , and  Wnt4  are dosage sensitive in B6 XY mice. We found that reduced  Wt1  or  Sf1  dosage in B6 XY B6  mice impaired testis differentiation, but no ovarian tissue developed. If, however, a Y AKR  chromosome replaced the Y B6  chromosome, these otherwise genetically identical B6 XY mice developed ovarian tissue. In contrast, reduced  Wnt4  dosage increased the amount of testicular tissue present in  Sf1 +/− B6 XY AKR ,  Wt1 +/− B6 XY AKR , B6 XY POS , and B6 XY AKR  fetuses. We propose that  Wt1 B6   and  Sf1 B6   are hypomorphic alleles of testis-determining pathway genes and that  Wnt4 B6   is a hypermorphic allele of an ovary-determining pathway gene. The latter hypothesis is supported by the finding that expression of  Wnt4  and four other genes in the ovary-determining pathway are elevated in normal B6 XX E12.5 ovaries. We propose that B6 mice are sensitive to XY sex reversal, at least in part, because they carry  Wt1 B6   and/or  Sf1 B6   alleles that compromise testis differentiation and a  Wnt4 B6   allele that promotes ovary differentiation and thereby antagonizes testis differentiation. Addition of a “weak”  Sry  allele, such as the one on the Y POS  chromosome, to the sensitized B6 background results in inappropriate development of ovarian tissue. We conclude that  Wt1 ,  Sf1 , and  Wnt4  are dosage-sensitive in mice, this dosage-sensitivity is genetic background-dependant, and the mouse strains described here are good models for the investigation of human dosage-sensitive XY sex reversal.

Sex Reversal in C57BL/6J XY Mice Caused by Increased Expression of Ovarian Genes and Insufficient Activation of the Testis Determining Pathway