Axial homeosis and appendicular skeleton defects in mice with a targeted disruption of hoxd-11.
Using gene targeting, we have created mice with a disruption in the homeobox-containing gene hoxd-11. Homozygous mutants are viable and the only outwardly apparent abnormality is male infertility. Skeletons of mutant mice show a homeotic transformation that repatterns the sacrum such that each vertebra adopts the structure of the next most anterior vertebra. Defects are also seen in the bones of the limb, including regional malformations at the distal end of the forelimb affecting the length and structure of phalanges and metacarpals, inappropriate fusions between wrist bones, and defects at the most distal end in the long bones of the radius and ulna. The phenotypes show both incomplete penetrance and variable expressivity. In contrast to the defects observed in the vertebral column, the phenotypes in the appendicular skeleton do not resemble homeotic transformations, but rather regional malformations in the shapes, length and segmentation of bones. Our results are discussed in the context of two other recent gene targeting studies involving the paralogous gene hoxa-11 and another member of the Hox D locus, hoxd-13. The position of these limb deformities reflects the temporal and structural colinearity of the Hox genes, such that inactivation of 3' genes has a more proximal phenotypic boundary (affecting both the zeugopod and autopod of the limb) than that of the more 5' genes (affecting only the autopod). Taken together, these observations suggest an important role for Hox genes in controlling localized growth of those cells that contribute to forming the appendicular skeleton.
Davis
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AP
Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City 84112.
Capecchi
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MR
D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities*; D005801:Genes, Homeobox / Q000235:genetics*; D017403:In Situ Hybridization; D017880:Limb Deformities, Congenital; D051379:Mice; D008822:Mice, Transgenic / Q000002:abnormalities* / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000502:physiology; D010641:Phenotype; D014170:Transformation, Genetic