Pleiotropic functions of Hox genes revealed by mutants for genes in Hox seventh and ninth paralogous groups

The mammalian Hox complex consists of 39 genes that are believed to control the regionalization of the embryo along its major body axes. To investigate the in vivo functions of Hox genes, mice individually mutant for a subset of Hox genes were generated by gene-targeting. Mice with mutations in genes on separate chromosomes were mated to generate multiple mutants to reveal redundant functions not apparent in individual mutants. The analysis of Hoxb9 mutants and Hoxa9/Hoxb9 double mutants demonstrates a role of Hoxb9 in the patterning of the thoracic region and a synergistic and quantitative interaction between Hoxa9 and Hoxb9. Although Hoxa7 mutants do not have any detectable phenotype, the functions of Hoxa7 in the patterning of the upper thoracic region became apparent in Hoxa7/Hoxb7 mutants, in which the effects of the disruption of Hoxb7 on the first two ribs were greatly exaggerated by the addition of the Hoxa7 mutant allele(s). The similarity of the defects found in the Hoxa7/Hoxb7 and Hoxa9/Hoxb9 mutants evokes a modification of the current hypothesis explaining the defects in the axial column in Hox mutants. Limb defects were observed when a Hoxd9 mutation was introduced into the Hoxa9/Hoxb9 mutants. Many triple mutant genotypes have overt forelimb defects caused mainly by a series of skeletal defects in the limb. In particular, the humerus was greatly reduced in length and altered in shape. Hox genes appear to confer positional cues to different portions of the vertebrate limb, as well as to regulate the growth of cells forming different structures of the limbs. Of particular interest, hypoplasia of the mammary gland has been observed in pregnant and lactating females with multiple mutations in Hoxa9, Hoxb9 and Hoxd9. This broadens our concept of Hox gene function from patterning of the developing embryo to include indispensable roles in adults.