Hox genes control antero-posterior patterning in vertebrates, but previous studies have failed to produce a definitive model of their influence on skeletal development. Research by Wellik and Capecchi now confirms their role as global regulators of the patterning of the vertebrate skeleton, and identifies specific functions for Hox10 and Hox11 in the development of the lower spine and hindlimbs.

Mice with mutations in single members or subsets of the paralogous Hox groups have only minor skeletal defects. Furthermore, combinations of mutations in any five of the six Hox10 or Hox11 alleles produce similar abnormalities, which indicates that individual alleles have roughly equivalent effects. By contrast, mutants in which all of these alleles have been inactivated have gross phenotypic defects.

By mutating all members of these functionally redundant groups, Wellik and Capecchi were able to determine their precise roles in patterning the axial skeleton: triple mutants of Hox10 lack lumbar vertebrae and develop ribs on all posterior vertebrae, whereas Hox11 triple mutants fail to develop sacral vertebrae.

In light of these findings, the authors propose a mechanism for how changes in Hox gene expression might have modified rib formation in the lumbo-sacral region during vertebrate evolution. Their data support the hypothesis that the ground state for this group is the presence of ribs on all vertebrae. Rostral or caudal shifts in the expression of Hox10 and Hox11 could have altered the number and position of thoracic and sacral vertebrae, resulting in the range of skeletal patterns seen across vertebrate species.

By highlighting the enormous functional overlap within paralogous Hox groups, Wellik and Capecchi have greatly improved our understanding of the role of these master genes in skeletal patterning. These results might also have potential implications for future studies of skeletal birth defects in humans.