C57BL/6J-T-associated sex reversal in mice is caused by reduced expression of a Mus domesticus Sry allele

Abstract

C57BL/6J-T-associated sex reversal (B6-TAS) in XY mice results in ovarian development and involves (1) hemizygosity for Tas, a gene located in the region of Chromosome 17 deleted in Thp and TOrl, (2) homozygosity for one or more B6-derived autosomal genes, and (3) the presence of the AKRY chromosome. Here we report results from experiments designed to investigate the Y chromosome component of this sex reversal. Testis development was restored in B6 TOrl/+ XYAKR mice carrying a Mus musculus Sry transgene. In addition, two functionally different classes of M. domesticus Sry alleles were identified among eight standard and two wild-derived inbred strains. One class, which includes AKR, did not initiate normal testis development in B6 TOrl/+ XYAKR mice, whereas the other did. DNA sequence analysis of the Sry ORF and a 5′ 800-bp segment divided these inbred strains into the same groups. Finally, we found that Sry is transcribed in B6 TOrl/+ XYAKR fetal gonads but at a reduced level. These results pinpoint Sry as the Y-linked component of B6-TAS. We hypothesize that the inability of specific M. domesticus Sry alleles to initiate normal testis development in B6 TOrl/+ XYAKR mice results from a biologically insufficient level of Sry expression, allowing the ovarian development pathway to proceed.