TARGETED MUTATIONS IN HOXA-9 AND HOXB-9 REVEAL SYNERGISTIC INTERACTIONS

Mice were generated with a targeted disruption of the homeobox-contain ing 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 pa irs of ribs normally attach to the sternum. Abnormalities of the stern um accompany the rib fusions. These include abnormal attachment of the ribs to the sternum, a reduction in the number of intercostal segment s of the sternum, and abnormal growth of the intercostal segments. Ove r half of the homozygous mutants, as well as some heterozygotes, also have an eighth rib attached to the sternum. These results show that ho xb-9 plays a significant role in the specification of thoracic skeleta l elements. To reveal potential interactions between the paralogous Ho x genes hoxa-9 and hoxb-9 mice heterozygous for both mutations were in tercrossed. Mice homozygous for both mutations show more severe phenot ypes than predicted by the addition of the individual mutant phenotype s. Both the penetrance and the expressivity of the rib and sternal def ects are increased, suggesting synergistic interactions between these genes. In particular, the sternum defects are greatly exacerbated. Int erestingly, the defects in hoxb-9 and hoxa-9/ hoxb-9 mutant mice are c oncentrated along the axial column at points of transition between ver tebral types. (C) 1997 Academic Press.