Wnt and Hedgehog signaling in vetebrate limb and skeleta

在脊椎动物胚胎发育早期，细胞-细胞信号传导起着重要作用。我们对Wnt和hedgehog信号通路在控制脊椎动物胚胎发育，特别是肢体发育和骨骼形态发生中的机制理解很感兴趣。在肢体发育早期，包括Wnt和hedgehog家族成员在内的信号分子决定了晚期结构（即骨骼元件）何时何地形成。肢体的骨骼形态发生是通过软骨内成骨发生的，软骨细胞（形成软骨）和成骨细胞（分泌骨基质）首先从间充质凝聚中分化出来。随后是软骨细胞和成骨细胞的顺序增殖和成熟，它们受到严格的调节和协调，以确保骨骼系统的适当形态发生。其潜在的分子机制近年来才刚刚开始被阐明。通过分析Wnt和hedgehog信号成分失活或异位表达的突变小鼠，我们发现Wnt5a与印度hedgehog基因（Ihh）和甲状旁腺激素相关肽（PTHrP）平行，是增殖型软骨细胞向增生性软骨细胞转变所必需的。通过小鼠遗传学和体外细胞和器官培养相结合的方法，我们正在研究Wnt5a通过其信号转导和与其他信号通路的串导来调节软骨细胞分化的机制。

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. The underlying molecular mechanism has just begun to be elucidated in recent years. Through analyzing mutant mice in which Wnt and hedgehog signaling components are either inactivated or ectopically expressed, we have found that 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). By a combined approaches of mouse genetics and in vitro cell and organ cultures, we are studying the mechanism by which Wnt5a transduce its signal and cross-talk with other signaling pathways to regulate chondrocyte differentiation.