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

Transfer of certain Mus domesticus-derived Y chromosomes (Sry DOM alleles, e.g., Sry POS and SryAKR) onto
the C57BL/6J (B6) mouse strain causes abnormal gonad development due to an aberrant interaction
between the Sry DOM 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 Sry DOM 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, Sry POS was expressed at about half the level of SryRIII whereas SryAKR and SryRIII were
equally expressed. On an F1 hybrid background, both Sry POS and SryRIII expression increased, but Sry POS
expression increased to a greater extent. Second, sexual development and Sr y expression levels were
determined in XX mice carrying a transgene expressing Sry POS 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.