Transgenic expression ofMap3k4rescuesT-associated sex reversal (Tas) in mice

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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, includingSOX9,WT1andMAP3K1. In contrast, XY sex reversal in mice usually requires complete absence of testis-determining gene products. One exception to this involvesT-associated sex reversal (Tas), a phenomenon characterized by the formation of ovotestes or ovaries in XY mice hemizygous for the hairpin-tail (Thp) orT-Orleans (TOrl) deletions on proximal mouse chromosome 17. We recently reported that mice heterozygous for a null allele ofMap3k4,which resides in theThpdeletion, exhibit XY ovotestis development and occasional gonadal sex reversal on the sensitized C57BL/6J-YAKR (B6-YAKR) genetic background, reminiscent of theTasphenotype. However, these experiments did not exclude the possibility that loss of other loci in theThpdeletion, or other effects of the deletion itself, might contribute toTas. Here, we show that disruption toSryexpression underlies XY gonadal defects in B6-YAKR embryos harbouring theThpdeletion and that a functionalMap3k4bacterial artificial chromosome rescues these abnormalities by re-establishing a normalSryexpression profile. These data demonstrate thatMap3k4haploinsufficiency is the cause ofT-associated sex reversal and that levels of this signalling molecule are a major determinant of the expression profile ofSry.

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