Hox11 paralogous genes are required for formation of wrist and ankle joints and articular surface organization.

Limb skeletal elements are connected by distinct synovial joints, but the mechanisms regulating joint formation, diversity, and organization remain unclear. Previous studies showed that Hox11 mouse mutants have severe developmental defects in radius and ulna and tibia and fibula, but wrist and ankle joint formation and characteristics were not examined in detail. We now find that E11.5 and E12.5 triple Hox11aaccdd mutants exhibit a significant reduction in prospective carpal and tarsal mesenchyme. Although the mesenchyme became segmented into individual carpal and tarsal skeletal elements with further development, the elements were ill defined and the more proximal elements (radiale, ulnare, talus, and calcaneous) actually underwent involution and/or fusion. Wild-type carpal and tarsal elements displayed a thick articulating superficial zone at their outer perimeter that expressed genes typical of developing joint interzones and articulating cells, including Gdf5, Erg, Gli3, collagen IIA, and lubricin, and defined each element anatomically. In mutant wrists and ankles, the superficial zone around each element was thin and ill defined, and expression of several of those genes was low and often interrupted. These and other data provide novel and clear evidence that Hox11 paralogous genes regulate wrist and ankle joint organization and are essential for establishing carpal and tarsal element boundary and maintaining their articulating surface tissue.