sex reversal in c57bl6j xy mice caused by increased expression of ovarian genes and insufficient activation of the testis determining pathway性逆转c57bl6j xy的增加引起的小鼠卵巢基因的表达和激活睾丸决定通路的不足.pdfVIP

Sex Reversal in C57BL/6J XY Mice Caused by Increased Expression of Ovarian Genes and Insufficient Activation of the Testis Determining Pathway 1 2 1 1 2,3 Stephanie M. Correa , Linda L. Washburn , Ravi S. Kahlon , Michelle C. Musson , Gerrit J. Bouma , Eva M. Eicher2, Kenneth H. Albrecht 1,2* 1 Department of Medicine, Biomedical Genetics, Boston University School of Medicine, Boston, Massachusetts, United States of America, 2 The Jackson Laboratory, Bar Harbor, Maine, United States of America, 3 Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America Abstract 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 XYB6 mice impaired testis differentiation, but no ovarian tissue developed. If, however, a YAKR chromosome replaced the YB6 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+/ 2 B6 XYAKR, Wt1+/ 2 B6 XYAKR, B6 XYPOS, and B6 XYAKR fetuses. We propose that Wt1B6 and Sf1B6 are hypomorphic alleles of testis- determining pathw