Male-to-female sex reversal in M33 mutant mice


Polycomb genes in Drosophila maintain the repressed state of homeotic and other developmentally regulated genes1,2,3,4 by mediating changes in higher-order chromatin structure5,6,7. M33, a mouse homologue of Polycomb, was isolated by means of the structural similarity of its chromodomain8. The fifth exon of M33 contains a region of homology shared by Drosophila and Xenopus8,9. In Drosophila, its deletion results in the loss of Polycomb function10. Here we have disrupted M33 in mice by inserting a poly(A) capture-type neor 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 gene11, 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.

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Figure 1: Targeted disruption of the M33 gene.
Figure 2: Male sex reversal in M33cterm/M33cterm adult mice.
Figure 3: Developmental analysis of gonads.
Figure 4: Skeletal analysis of M33cterm/M33cterm newborn.


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We thank T. Takeuchi, Y. Takihara, H. Koseki and T. Akasaka for advice and discussion; M. Djabali for communicating unpublished results; and R. A. Shiurba for critical reading of the manuscript.

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Correspondence to Yuko Katoh-Fukui.

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Katoh-Fukui, Y., Tsuchiya, R., Shiroishi, T. et al. Male-to-female sex reversal in M33 mutant mice. Nature 393, 688–692 (1998).

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