Transgenic expression of Map3k4 rescues T-associated sex reversal (Tas

Disorders of sex development in the human population range in severity from mild genital defects to gonadal sex reversal. XY female development has been associated with heterozygous mutations in several genes, including SOX9,WT1 andMAP3K1. In contrast, XY sex reversal in mice usually requires complete absence of testis-deter-mining gene products. One exception to this involvesT-associated sex reversal (Tas), a phenomenon character-ized by the formation of ovotestes or ovaries in XY mice hemizygous for the hairpin-tail (Thp) or T-Orleans (TOrl) deletions on proximal mouse chromosome 17. We recently reported that mice heterozygous for a null allele of Map3k4,which resides in the Thp deletion, exhibit XY ovotestis development and occasional gonadal sex rever-salon thesensitized C57BL/6J-YAKR (B6-YAKR)geneticbackground, reminiscentof theTasphenotype. However, these experiments did not exclude the possibility that loss of other loci in theThp deletion, or other effects of the deletion itself, might contribute to Tas. Here, we show that disruption to Sry expression underlies XY gonadal defects in B6-YAKR embryos harbouring theThpdeletion and that a functionalMap3k4bacterial artificial chromo-some rescues these abnormalities by re-establishing a normal Sry expression profile. These data demonstrate that Map3k4 haploinsufficiency is the cause of T-associated sex reversal and that levels of this signalling mol-ecule are a major determinant of the expression profile of Sry