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

Hum Mol Genet. 2014 Jun 1;23(11):3035-44. doi: 10.1093/hmg/ddu020. Epub 2014 Jan 22.

Abstract

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 and MAP3K1. In contrast, XY sex reversal in mice usually requires complete absence of testis-determining gene products. One exception to this involves T-associated sex reversal (Tas), a phenomenon characterized by the formation of ovotestes or ovaries in XY mice hemizygous for the hairpin-tail (T(hp)) or T-Orleans (T(Orl)) deletions on proximal mouse chromosome 17. We recently reported that mice heterozygous for a null allele of Map3k4, which resides in the T(hp) deletion, exhibit XY ovotestis development and occasional gonadal sex reversal on the sensitized C57BL/6J-Y(AKR) (B6-Y(AKR)) genetic background, reminiscent of the Tas phenotype. However, these experiments did not exclude the possibility that loss of other loci in the T(hp) 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-Y(AKR) embryos harbouring the T(hp) deletion and that a functional Map3k4 bacterial artificial chromosome 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 molecule are a major determinant of the expression profile of Sry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disorders of Sex Development / enzymology*
  • Disorders of Sex Development / genetics
  • Female
  • Humans
  • MAP Kinase Kinase Kinase 4 / genetics
  • MAP Kinase Kinase Kinase 4 / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Ovary / metabolism
  • Sex Determination Processes*
  • Testis / metabolism

Substances

  • MAP Kinase Kinase Kinase 4
  • MAP3K4 protein, human
  • Map3k4 protein, mouse