ALTERED CELLULAR PROLIFERATION AND MESODERM PATTERNING IN POLYCOMB-M33-DEFICIENT MICE

In Drosophila, the trithorax-group and the Polycomb-group genes are ne cessary to maintain the expression of the homeobox genes in the approp riate segments. Loss-of-function mutations in those groups of genes le ad to misexpression of the homeotic genes resulting in segmental homeo tic transformations. Recently, mouse homologues of the Polycomb-group genes were identified including M33, the murine counterpart of Polycom b. In this report, M33 was targeted in mice by homologous recombinatio n in embryonic stem (ES) cells to assess its function during developme nt. Homozygous M33 (-/-) mice show greatly retarded growth, homeotic t ransformations of the axial skeleton, sternal and limb malformations a nd a failure to expand in vitro of several cell types including lympho cytes and fibroblasts. In addition, M33 null mutant mice show an aggra vation of the skeletal malformations when treated to RA at embryonic d ay 7.5, leading to the hypothesis that, during development, the M33 ge ne might play a role in defining access to retinoic acid response elem ents localised in the regulatory regions of several Hox genes.