Mice homozygous for a targeted disruption of Hoxd-3 (Hox-4.1) exhibit anterior 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 craniocervical joint. The anterior arch of the atlas is transformed to an extension of the basioccipital bone of the skull. The lateral masses of the atlas also assume a morphology more closely resembling the exoccipitals 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 function. Some parts are deleted, others are homeotically transformed to more anterior structures. These observations suggest that one role of Hox genes may be to differentially control the proliferation rates of the mesenchymal condensations that give rise to the vertebral cartilages. Within the mouse Hox complex, paralogous genes not only encode very similar proteins but also often exhibit very similar expression patterns. Therefore, it has been postulated that paralogous Hox genes would perform similar roles. Surprisingly, however, no tissues or structures are affected in common by mutations in the two paralogous genes, Hoxa-3 and Hoxd-3.

Further studies on skull growth in achondroplasic (cn) mice

The morphology of the basioccipital, basisphenoid and mandibular bones in achondroplasic (cn/cn) mice was compared with that of normal siblings. The two bones of the cranial base were markedly reduced in length but not in width. The percentage reduction in the basisphenoid was twice that in the basioccipital bone and of the same magnitude as that previously observed in the long bones of the limbs. This difference may arise because the basisphenoid, like the long bones, grows in length from two cartilaginous growth sites while the basioccipital grows from one cartilaginous and one periosteal site. The mandible of the (cn/cn) mice was also reduced in size, although to a lesser extent than were the cranial bones and without the ensuing disproportion. The scale of the mandibular changes suggests that they are largely attributable to regulatory responses to the shortened cranium. The finding that the condylar cartilage of the cn/cn mice is reduced in thickness indicates, however, that the cn gene may have a direct effect on condylar chondrocytes.