The structures that encase the central nervous system - the vertebra and the skull - develop from somitic mesoderm and from the neural crest. The molecular mechanisms that underlie this developmental process have not been studied widely. We have obtained a murine transgenic insertional mutation with a recessive phenotype characterized by hemivertebrae, vertebral fusions, and fusions between skull and atlas. We now have determined that the insertion occurred in the first intron of the mesodermal homeodomain gene mox1. This gene is expressed in mesoderm as early as the primitive streak stage and later in presomitic mesoderm, differentiating somites, and mesenchyme of the heart cushion, truncus arteriosus and craniofacial neural crest. The insertion was accompanied by a deletion extending beyond the 3' end of the gene. However, genomic P1 clones that contain the entire mox1 gene plus additional 3' sequences have allowed us to span the deletion. Since there is no evidence for additional gross rearrangements or deletions in the chromosomal area surrounding the insertion, it is likely that the phenotype is due solely to the disruption of the mox1 gene. The phenotype is consistent with a role of mox1 in the formation of preskeletal condensations and indicates that related homeodomain proteins such as mox2 with partly overlapping expression patterns are not able to compensate for the loss of mox1. Future studies will show whether the role of mox1 is primarily in regulating growth rates of mesenchymal cells, thus specifying the time points and locations of condensations and the formation of ossification centers, or has additional function in specifying the identity of structures of the axial skeleton. The results will have impact on understanding skeletal and skull malformations in mice and humans as well.
