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Mice in which all members of the Hox10 or Hox11 paralogous group are disrupted provide evidence that these Hox genes are involved in global patterning of the axial and appendicular skeleton. In the absence of Hox10 function, no lumbar vertebrae are formed. Instead, ribs project from all posterior vertebrae, extending caudally from the last thoracic vertebrae to beyond the sacral region. In the absence of Hox11 function, sacral vertebrae are not formed and instead these vertebrae assume a lumbar identity. The redundancy among these paralogous family members is so great that this global aspect of Hox patterning is not apparent in mice that are mutant for five of the six paralogous alleles.
Hox genes have long been recognized as important transcriptional regulators of embryonic development. In mammals, this complex of 39 genes resides on four separate chromosomal linkage groups designated A, B, C, and D, which arose early in the evolution of vertebrates from successive duplications of a single ancestral complex. Homologous members within the separate linkage groups are divided into 13 sets of paralogous genes, each having two to four members. During development, paralogous sets of genes are activated sequentially, with Hox1 and Hox2 paralogous genes being expressed earlier and more anteriorly in the embryo and successive genes through paralogous group Hox13 appearing later and more posteriorly.
The spectrum of perturbations of the mammalian skeleton resulting from either gain- or loss-of-function mutations in individual Hox genes has been difficult to interpret in terms of a coherent model of how these genes participate in the patterning of the axial skeleton. Loss-of-function Hox mutations have yielded changes in vertebral morphology along the anteroposterior (AP) axis that have been interpreted as anterior homeotic transformations as well as posterior homeotic transformations. Typically, these morphological changes involve perturbations in one or a small number of vertebrae.
Among different vertebrate species, axial skeletal patterns have diverged considerably. A comparative survey of Hox gene expression in mice and chicks showed that Hox gene expression boundaries along the rostrocaudal axis shift in accordance with changes in the class of vertebrae produced at a given axial level (1). This observation suggests that Hox genes play a critical role in the global patterning of the vertebrate axial skeleton (2). Yet, over the past...