TARGETED DISRUPTIONS OF THE MURINE HOXA-4 AND HOXA-6 GENES RESULT IN HOMEOTIC TRANSFORMATIONS OF COMPONENTS OF THE VERTEBRAL COLUMN

It is becoming clear that Hox genes, which encode transcription factor s of the Antennapedia homeodomain family, are key players in establish ing the body plan of mammalian embryos. They have already been implica ted in the formation of the central nervous system, tissues derived fr om neural crest, the vertebral column and the limbs. In order to exami ne the roles of hoxa-4 and hoxa-6 during development, mice with target ed disruptions in these genes were generated. Each shows homeotic tran sformation of cervical vertebrae, at positions that approximate the an terior borders of expression of these genes in the prevertebrae. Defec ts were not observed in other tissues that normally express these gene s. Hoxa-4(-)/hoxa-4(-) mice show, with 100% penetrance, anterior trans formations of the dorsal aspects of the third cervical vertebra by acq uiring features normally associated with the second cervical vertebra. Mice homozygous for the hoxa-6 mutation show, with incomplete penetra nce, even on opposite sides of the same animal, posterior transformati ons of the seventh cervical vertebra to the first thoracic vertebra. I n addition, both hoxa-4(-)/hoxa-4(-) and hoxa-6(-)/hoxa-6(-) mice show variability in expressivity. These data indicate that alternative gen etic pathways can partially, and at times completely, substitute for t he function of these two genes. Other members of these two paralogous Hox families are good candidates for providing the substitutions. As p aralogous genes lie on different chromosomes, it is possible to examin e the degree of redundancy among these genes by intercrossing mice wit h the appropriate individual disruptions. The analysis of double, trip le and even quadruple mutants should determine the ways in which these Hox genes interact in order to specify the multitude of tissues in a restricted region of the developing mouse embryo.