MICE HOMOZYGOUS FOR A TARGETED DISRUPTION OF HOXD-3 (HOX-4.1) EXHIBITANTERIOR TRANSFORMATIONS OF THE FIRST AND SECOND CERVICAL-VERTEBRAE, THE ATLAS AND THE AXIS

Gene targeting in embryo-derived stem (ES) cells was used to generate mice with a disruption in the homeobox-containing gene Hoxd-3 (Hox-4.1 ). Mice homozygous for this mutation show a radically remodeled cranio cervical joint. The anterior arch of the atlas is transformed to an ex tension of the basioccipital bone of the skull. The lateral masses of the atlas also assume a morphology more closely resembling the exoccip itals and, to a variable extent, fuse with the exoccipitals. Formation of the second cervical vertebra, the axis, is also affected. The dens and the superior facets are deleted, and the axis shows 'atlas-like' characteristics. An unexpected observation is that different parts of the same vertebra are differentially affected by the loss of Hoxd-3 fu nction. Some parts are deleted, others are homeotically transformed to more anterior structures. These observations suggest that one role of Hox genes may be to differentally control the proliferation rates of the mesenchymal condensations that give rise to the vertebral cartilag es. Within the mouse Hox complex, paralogous genes not only encode ver y similar proteins but also often exhibit very similar expression patt erns. Therefore, it has been postulated that paralogous Hox genes woul d perform similar roles. Surprisingly, however, no tissues or structur es are affected in common by mutations in the two paralogous genes, Ho xa-3 and Hoxd-3.