International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

G8 Misregulation of Sry in C57BL/6J-YPOS Sex Reversal

Kenneth H. Albrecht, Linda L. Washburn and Eva M. Eicher. The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609

The initiation of mammalian testis development is controlled by the Y chromosome Sry (sex determining region, Y chromosome) gene that acts as a classical genetic switch to divert the undifferentiated bipotential gonad to the testis development pathway. Sry encodes an HMG domain DNA binding protein and probably is a transcription factor that regulates other genes in the sex determination pathway. Formal proof that Sry encodes the testis determining gene came from transgenic experiments: XX mice carrying a 14.6 kb genomic DNA fragment, containing only Sry, were sex reversed males.

In mice, transfer of certain Mus domesticus-derived Y chromosomes onto the C57BL/6J (B6) inbred strain results in ovarian tissue development in XY individuals. B6-YPOS sex reversal is the founding member of this type of sex reversal and has proven to be genetically complex, resulting from an aberrant interaction between the M. domesticus poschiavinus-derived Sry allele and B6-derived autosomal genes (i.e., tda genes).

Comparative sequence analysis of Sry alleles and examination of testis development in various B6-YM. domesticus consomic strains indicated no correlation between the different protein isoforms and sex reversal. These data suggest the cause of B6-YPOS sex reversal is not solely the Sry protein, but rather largely the misregulation of SRY expression. To directly test this hypothesis, we generated B6 transgenic mouse lines carrying a chimeric Sry transgene created by substituting the open reading frame (and part of the 3' UTR) from SryPOS into the M. musculus-derived 14.6 kb Sry clone (from the 129 strain). In this chimeric construct, expression of Sry protein from the sex reversing SryPOS allele is driven by the regulatory regions from a normal sex determining Sry 129 allele. We found that B6 XX mice carrying this chimeric transgene develop only testicular tissue. However, the initial development of testis cords is delayed despite overexpression of Sry. These data suggest delayed testis cord development is caused by SRY protein isoform differences and Sry misregulation "pushes" this delay into sex reversal in B6 XYPOS gonads.

To further investigate Sry misregulation in B6-YPOS sex reversal, we constructed a B6 strain carrying a single copy each of a M. domesticus-derived and a M. musculus-derived Sry allele (B6-YPOS,Sxr). B6 XYPOS,Sxr mice develop normal testes. Data generated using a quantitative RT-PCR assay indicates that the SryPOS allele is expressed at lower levels than the SrySxr allele in B6 XYPOS,Sxr fetal gonads. However, the relative expression of the SryPOS allele is increased in (DBA x B6 XYPOS,Sxr )F1 XYPOS,Sxr fetal gonads. These data suggest that at least one tda gene regulates the level of Sry expression.


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