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.