TARGETED DISRUPTION OF HOXD-10 AFFECTS MOUSE HINDLIMB DEVELOPMENT

Targeted disruption of the Hoxd-10 gene, a 5' member of the mouse HoxD linkage group, produces mice with hindlimb-specific defects in gait a nd adduction, To determine the underlying causes of this locomotor def ect, mutant mice were examined for skeletal, muscular and neural abnor malities. Mutant mice exhibit alterations in the vertebral column and in the bones of the hindlimb. Sacral vertebrae beginning at the level of S2 exhibit homeotic transformations to adopt the morphology of the nest most anterior vertebra. In the hindlimb, there is an anterior shi ft in the position of the patella, an occasional production of an ante rior sesamoid bone, and an outward rotation of the lower part of the l eg, all of which contribute to the defects in locomotion. No major alt erations in hindlimb musculature were observed, but defects in the ner vous system were evident, There was a decrease in the number of spinal segments projecting nerve fibers through the sacral plexus to innerva te the musculature of the hindlimb. Deletion of a hindlimb nerve was s een in some animals, and a shift was evident in the position of the lu mbar lateral motor column. These observations suggest a role for the H oxd-10 gene in establishing regional identity within the spinal cord a nd imply that patterning of the spinal cord may have intrinsic compone nts and is not completely imposed by the surrounding mesoderm.