Early in vertebrate embryonic development, cell-cell signaling plays important roles. We are interested in the mechanistic understanding of Wnt and hedgehog signaling pathways in the control of vertebrate embryonic development, in particular, limb development and skeletal morphogeneis. Early in limb development, signaling molecules which include the Wnt and hedgehog family members determines where and when the late structures, ie, skeletal elements will form. Skeletal morphogeneis in the limb occurs through endochondral bone formation in which chondrocytes (they form the cartilage) and osteoblasts (they secrete bone matrix) are first differentiated from mesenchymal condensations. This is followed by sequential proliferation and maturation of both chondrocytes and osteoblasts, which are tightly regulated and coordinated to ensure proper morphogenesis of the skeletal system. Through analyzing mutant mice in which Wnt and hedgehog signaling components are either inactivated or ectopically expressed, we have found that in the Wnt family, Wnt5a is required for the transition from proliferative chondrocytes to prehypertrophic chondrocytes in a pathway in parallel with Indian Hedgehog (Ihh) and parathyroid hormone related peptide.(PTHrP). In addition, We have found that important cell cycle regulators such as Cyclin D1 and p130, a member of the retinoblastoma family exhibit complimentary expression patterns that correlate with the distinct proliferation and differentiation states of chondrocyte zones. Furthermore, we show that Wnt5a and Wnt5b appear to coordinate chondrocyte proliferation and differentiation by differentially regulating Cyclin D1 and p130 expression as well as chondrocyte-specific ColII expression. Our data indicate that Wnt5a and Wnt5b control the pace of transitions between different chondrocyte zones. Through a combined approaches of mouse genetics and in vitro cell and organ cultures, we are studying the mechanism by which Wnt5a transduces its signal and cross-talk with other signaling pathways in regulating embryonic development. We have found that Wnt5a, in contrast to many other Wnts, signal through a novel pathway to antagonize the canonic Wnt pathway in regulating embryonic development and possibly in suppressing tumor formation.