Sry Expression Level and Protein Isoform Differences Play a Role in Abnormal Testis Development in C57BL/6J Mice Carrying Certain Sry Alleles

Abstract

Abstract Transfer of certain Mus domesticus-derived Y chromosomes (SryDOM alleles, e.g., SryPOS and SryAKR) onto the C57BL/6J (B6) mouse strain causes abnormal gonad development due to an aberrant interaction between the SryDOM allele and the B6-derived autosomal (tda) genes. For example, B6 XYPOS fetuses develop ovaries and ovotestes and B6 XYAKR fetuses have delayed testis cord development. To test whether abnormal testis development is caused by insufficient SryDOM expression, two approaches were used. First, gonad development and relative Sry expression levels were examined in fetal gonads from two strains of B6 mice that contained a single M. domesticus-derived and a single M. musculus-derived Sry allele (B6-YPOS,RIII and B6-YAKR,RIII). In both cases, presence of the M. musculus SryRIII allele corrected abnormal testis development. On the B6 background, SryPOS was expressed at about half the level of SryRIII whereas SryAKR and SryRIII were equally expressed. On an F1 hybrid background, both SryPOS and SryRIII expression increased, but SryPOS expression increased to a greater extent. Second, sexual development and Sry expression levels were determined in XX mice carrying a transgene expressing SryPOS controlled by POS-derived or MUS-derived regulatory regions. In both cases one B6 transgenic line was recovered in which XX transgenic mice developed only testicular tissue but cord development was delayed despite normal Sry transcriptional initiation and overexpression. For three transgenes where B6 XX transgenic mice developed as females, hermaphrodites, or males, the percentage of XX transgenic males increased on an F1 background. For the one transgene examined, Sry expression increased on an F1 background. These results support a model in which delayed testis development is caused by the presence of particular DOM SRY protein isoforms and this, combined with insufficient Sry expression, causes sex reversal. These results also indicate that at least one tda gene regulates Sry expression, possibly by directly binding to Sry regulatory regions.