COMPOUND MUTANTS FOR THE PARALOGOUS HOXA-4, HOXB-4, AND HOXD-4 GENES SHOW MORE COMPLETE HOMEOTIC TRANSFORMATIONS AND A DOSE-DEPENDENT INCREASE IN THE NUMBER OF VERTEBRAE TRANSFORMED

The Hox gene products are transcription factors involved in specifying regional identity along the anteroposterior body axis. In the mouse, several single mutants for Hox genes show variably penetrant, partial homeotic transformations of vertebrae at their anterior limits of expr ession, suggesting that compound Hox mutants might show more complete transformations with greater penetrance than the single Hox mutants. C ompound mutants for the paralogous group 3 genes, hoxa-3 and hoxd-3, s how deletion of a cervical vertebrae, which is not readily interpretab le in terms of an alteration in regional identity. Here, we report the skeletal phenotypes of compound mutants in the group 4 Hox genes, hox a-4, hoxb-4, and hoxd-4. Mice mutant for each of these genes were inte rcrossed to generate the three possible double mutant combinations and the triple mutant. In contrast to the hoxa-3, hoxd-3 double mutants, group 4 Hox compound mutants displayed clear alterations in regional i dentity, including a nearly complete transformation of the second cerv ical vertebrae toward the morphology of the first cervical vertebra in one double mutant combination. In comparing the types of homeotic tra nsformations observed, different double mutant combinations showed dif ferent degrees of synergism. These results suggest a certain degree of functional redundancy among paralogous genes in specifying regional i dentity. Furthermore, there was a remarkable dose-dependent increase i n the number of vertebrae transformed to a first cervical vertebra ide ntity, including the second through the fifth cervical vertebrae in th e triple mutant. Thus, these genes are required in a larger anteropost erior domain than is revealed by the single mutant phenotypes alone, s uch that multiple mutations in these genes result in transformations o f vertebrae that are not at their anterior limit of expression.