A ROLE FOR MEL-18, A POLYCOMB GROUP-RELATED VERTEBRATE GENE, DURING THE ANTEROPOSTERIOR SPECIFICATION OF THE AXIAL SKELETON

Segment identity in both invertebrates and vertebrates is conferred by spatially restricted distribution of homeotic gene products. In Droso phila, the expression of Homeobox genes during embryogenesis is initia lly induced by segmentation gene products and then maintained by Polyc omb group and Trithorax group gene products, Polycomb group gene homol ogs are conserved in vertebrates, Murine mel-18 and closely related bm i-l are homologous to posterior sex combs and suppressor two of zeste, Mel-18 protein mediates a transcriptional repression via direct bindi ng to specific DNA sequences, To gain further insight into the functio n of Mel-18, we have inactivated the mel-Ig locus by homologous recomb ination, Mice lacking mel-18 survive to birth and die around 4 weeks a fter birth after exhibiting strong growth retardation. Similar to the Drosophila posterior sex combs mutant, posterior transformations of th e axial skeleton were reproducibly observed in mel-18 mutants. The hom eotic transformations were correlated with ectopic expression of Homeo box cluster genes along the anteroposterior axis in the developing par axial mesoderm, Surprisingly, mel-18-deficient phenotypes are reminisc ent of bmi-1 mutants, These results indicate that the vertebrate Polyc omb group genes mel-18 and bmi-1, like Drosophila Polycomb group gene products, might play a crucial role in maintaining the silent state of Homeobox gene expression during paraxial mesoderm development.