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 Sf 1 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. © 2012 Correa et al.
Correa, S. M., Washburn, L. L., Kahlon, R. S., Musson, M. C., Bouma, G. J., Eicher, E. M., & Albrecht, K. H. (2012). Sex reversal in C57BL/6J XY mice caused by increased expression of ovarian genes and insufficient activation of the testis determining pathway. PLoS Genetics, 8(4). https://doi.org/10.1371/journal.pgen.1002569