Male-to-female sex reversal in M33 mutant mice

Nature. 1998 Jun 18;393(6686):688-92. doi: 10.1038/31482.


Polycomb genes in Drosophila maintain the repressed state of homeotic and other developmentally regulated genes by mediating changes in higher-order chromatin structure. M33, a mouse homologue of Polycomb, was isolated by means of the structural similarity of its chromodomain. The fifth exon of M33 contains a region of homology shared by Drosophila and Xenopus. In Drosophila, its deletion results in the loss of Polycomb function. Here we have disrupted M33 in mice by inserting a poly(A) capture-type neo(r) targeting vector into its fifth exon. More than half of the resultant M33cterm/M33cterm mutant mice died before weaning, and survivors showed male-to-female sex reversal. Formation of genital ridges was retarded in both XX and XY M33cterm/M33cterm embryos. Gonadal growth defects appeared near the time of expression of the Y-chromosome-specific Sry gene, suggesting that M33 deficiency may cause sex reversal by interfering with steps upstream of Sry. M33cterm/M33cterm mice may be a valuable model in which to test opposing views regarding sex determination.

MeSH terms

  • Animals
  • Chimera
  • Disorders of Sex Development*
  • Female
  • Genes, Recessive
  • Genitalia / abnormalities
  • Genitalia / embryology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Ovary / embryology
  • Polycomb Repressive Complex 1
  • Polycomb-Group Proteins
  • Repressor Proteins / genetics*
  • Sex Determination Processes
  • Stem Cells
  • Testis / embryology


  • Cbx2 protein, mouse
  • Polycomb-Group Proteins
  • Repressor Proteins
  • Polycomb Repressive Complex 1