A transgenic insertion upstream of Sox9 is associated with dominant XX sexreversal in the mouse

In most mammals, male development is triggered by the transient expression of the Y-chromosome gene, Sry, which initiates a cascade of gene interactio ns ultimately leading to the formation of a testis from the indifferent fet al gonad(1-4). Several genes(5-8), in particular Sox9, have a crucial role in this pathway(9-14). Despite this, the direct downstream targets of Sry a nd the nature of the pathway itself remain to he clearly established(15,16) . We report here a new dominant insertional mutation, Odsex (Ods), in which XX mice carrying a 150-kb deletion (approximately 1 Mb upstream of Sox9) d evelop as sterile XX males lacking Sry, During embryogenesis, wild-type XX fetal gonads downregulate Sox9 expression, whereas XY and XX Ods/+ fetal go nads upregulate and maintain its expression(13,14). We propose that Ods has removed a long-range, gonad-specific regulatory element that mediates the repression of Sox9 expression in XX fetal gonads. This repression would nor mally be antagonized by Sry protein in XY embryos. Our data ate consistent with Sox9 being a direct downstream target of Sry and provide genetic evide nce to support a general repressor model of sex determination in mammals(17 ,18).