ABSENCE OF RADIUS AND ULNA IN MICE LACKING HOXA-11 AND HOXD-11

MICE with targeted disruptions(1) in Hox genes have been generated to evaluate the role of the Hox complex in determining the mammalian body plan. This complex of 38 genes encodes transcription factors that spe cify regional information along the embryonic axes. Early in vertebrat e evolution an ancestral complex shared with invertebrates was duplica ted twice to give rise to the four linkage groups (Hox A, B, C and D)( 2,3). As a consequence, corresponding genes on the separate linkage gr oups, called paralogues, are most closely related to each other. Based on sequence similarities, the Hox genes have been subdivided into 13 paralogous groups. The five most 5' groups (Hox 9-13) pattern the post erior region of the vertebrate embryo and the appendicular skeleton(4- 18). Mice with individual mutations in the paralogous genes hoxa-11 an d hoxd-11 have been described(15-18). By breeding these two strains to gether we have generated double mutants which have dramatic phenotypes not apparent in mice homozygous for the individual mutations. The rad ius and the ulna of the forelimb are almost entirely eliminated, the a xial skeleton shows homeotic transformations, and there are severe kid ney defects not present in either single mutant. The limb and axial ph enotypes are quantitative: as more mutant alleles are added to the gen otype, the phenotype becomes progressively more severe. The appendicul ar skeleton defects suggest that paralogous Hox genes function togethe r to specify limb outgrowth and patterning along the proximodistal axi s.