Male-to-female sex reversal in M33 mutant mice

Polycomb genes in Drosophila maintain the repressed state of homeotic and other developmentally regulated genes(1-4) by mediating changes in higher-order chromatin structure(5-7). M33, a mouse homologue of Polycomb, was isolated by means of the structural similarity of its chromodomain(8). The fifth exon of M33 contains a region of homology shared by Drosophila and Xenopus(8,9). In Drosophila, its deletion results in the loss of Polycomb function(10). 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 M33(cterm)/M33(cterm) mutant mice died before weaning, and survivors showed male-to-female sex reversal. Formation of genital ridges was retarded in both XX and XY M33(cterm)/M33(cterm) embryos. Gonadal growth defects appeared near the time of expression of the Y-chromosome-specific Sry gene(11), suggesting that M33 deficiency may cause sex reversal by interfering with steps upstream of Sry. M33(cterm)\M33(cterm) mice may be a valuable model in which to test opposing views regarding sex determination.