Hox11 genes are required for regional patterning and integration of muscle, tendon and bone

Development of the musculoskeletal system requires precise integration of muscles, tendons and bones. The molecular mechanisms involved in the differentiation of each of these tissues have been the focus of significant research; however, much less is known about how these tissues are integrated into a functional unit appropriate for each body position and role. Previous reports have demonstrated crucial roles for Hox genes in patterning the axial and limb skeleton. Loss of Hox11 paralogous gene function results in dramatic malformation of limb zeugopod skeletal elements, the radius/ulna and tibia/fibula, as well as transformation of the sacral region to a lumbar phenotype. Utilizing a Hoxa11eGFP knock-in allele, we show that Hox11 genes are expressed in the connective tissue fibroblasts of the outer perichondrium, tendons and muscle connective tissue of the zeugopod region throughout all stages of development. Hox11 genes are not expressed in differentiated cartilage or bone, or in vascular or muscle cells in these regions. Loss of Hox11 genes disrupts regional muscle and tendon patterning of the limb in addition to affecting skeletal patterning. The tendon and muscle defects in Hox11 mutants are independent of skeletal patterning events as disruption of tendon and muscle patterning is observed in Hox11 compound mutants that do not have a skeletal phenotype. Thus, Hox genes are not simply regulators of skeletal morphology as previously thought, but are key factors that regulate regional patterning and integration of the musculoskeletal system.