Altered retinoic acid sensitivity and temporal expression of Hox genes in Polycomb-M33-deficient mice

The Polycomb group genes are required for the correct expression of the hom eotic complex genes and segment specification during Drosophila embryogenes is and larval development. In mouse, inactivation studies of several Polyco mb group genes indicate that they are also involved in Hox gene regulation. We have used our previously generated M33 mutants to study the function of M33, the mouse homologue of the Polycomb gene of Drosophila. In this paper , we show that in the absence of M33, the window of Hoxd4 retinoic acid (RA ) responsiveness is opened earlier and that Hoxd11 gene expression is activ ated earlier in development This indicates that M33 antagonizes the RA path way and has a function in the establishment of the early temporal sequence of activation of Hox genes. Despite the early activation, A-P boundaries ar e correct in later stages, indicating a separate control mechanism for earl y aspects of Hox regulation. This raises a number of interesting issues wit h respect to the roles of both Pc-G proteins and Hox regulatory mechanisms. We propose that a function of the M33 protein is to control the accessibil ity of retinoic acid response elements in the vicinity of Hox genes regulat ory regions by direct or indirect mechanisms or both. This could provide a means for preventing ectopic transactivation early in development and be pa rt of the molecular basis for temporal colinearity of Hox gene expression. (C) 2000 Academic Press.