Targeted mutations in hoxa-9 and hoxb-9 reveal synergistic interactions.

Mice were generated with a targeted disruption of the homeobox-containing gene hoxb-9. Mice homozygous for this mutation show defects in the development of the first and second ribs. In most cases the first and second ribs are fused near the point at which the first and second pairs of ribs normally attach to the sternum. Abnormalities of the sternum accompany the rib fusions. These include abnormal attachment of the ribs to the sternum, a reduction in the number of intercostal segments of the sternum, and abnormal growth of the intercostal segments. Over half of the homozygous mutants, as well as some heterozygotes, also have an eighth rib attached to the sternum. These results show that hoxb-9 plays a significant role in the specification of thoracic skeletal elements. To reveal potential interactions between the paralogous Hox genes hoxa-9 and hoxb-9, mice heterozygous for both mutations were intercrossed. Mice homozygous for both mutations show more severe phenotypes than predicted by the addition of the individual mutant phenotypes. Both the penetrance and the expressivity of the rib and sternal defects are increased, suggesting synergistic interactions between these genes. In particular, the sternum defects are greatly exacerbated. Interestingly, the defects in hoxb-9 and hoxa-9/ hoxb-9 mutant mice are concentrated along the axial column at points of transition between vertebral types.