HOMEOTIC TRANSFORMATIONS AND LIMB DEFECTS IN HOX-A11 MUTANT MICE

Hox A11 is one of the expanded set of vertebrate homeo box (Hox) genes with similarities to the Drosophila homeotic gene, Abdominal-B (Abd-B). These Abd-B-type Hox genes have been shown to be expressed in the most caudal regions of the developing vertebrate embryo and in overlapping domains within the developing limbs, suggesting that these genes play important roles in pattern formation in both appendicular and axial regions of the body. In this report whole-mount in situ hybridization in mouse embryos gave a precise description of Hox A11 gene expression in the developing limbs and in the axial domain of the developing body. In addition, we generated a targeted mutation in Hox A11 and characterized the resulting phenotype to begin to dissect developmental functions of the Abd-B subfamily of Hox genes. Hox A11 mutant mice exhibited double homeotic transformations, with the thirteenth thoracic segment posteriorized to form an additional first lumbar vertebra and with the sacral region anteriorized, generating yet another lumbar segment. Furthermore, skeletal malformations were observed in both forelimbs and hindlimbs. In mutant forelimbs, the ulna and radius were misshapen, the pisiform and triangular carpal bones were fused, and abnormal sesamoid bone development occurred. In mutant hindlimbs the tibia and fibula were joined incorrectly and malformed at their distal ends. Also, an enlarged sesamoid developed ventral to the tibiale bone. Both heterozygous and homozygous mice displayed mutant phenotypes adding an additional level of complexity to the Hox code hypothesis.