Wnt and Hedgehog signaling in vetebrate limb and skeleta

在脊椎动物胚胎发育的早期，细胞-细胞信号转导起着重要作用。我们感兴趣的是Wnt和Hedgehog信号通路在脊椎动物胚胎发育，特别是肢体发育和骨骼形态发生控制中的作用机制。在肢体发育的早期，包括Wnt和Hedgehog家族成员在内的信号分子决定了晚期结构(即骨骼元素)形成的地点和时间。肢体的骨骼形态形成是通过软骨内成骨发生的，其中软骨细胞(它们形成软骨)和成骨细胞(它们分泌骨基质)首先从间充质凝聚中分化出来。紧随其后的是软骨细胞和成骨细胞的连续增殖和成熟，它们受到严格的调控和协调，以确保骨骼系统的适当形态发生。通过对Wnt信号成分失活或异位表达的突变小鼠的分析，我们发现Wnt5a与许多其他Wnts不同，它通过一种新的途径来拮抗经典的Wnt途径来调节胚胎发育和可能抑制肿瘤的形成。此外，我们还发现在发育中的滑膜关节中，几个Wnt基因以重叠和互补的模式表达，其中？-catenin蛋白水平和转录活性上调。早期去除间充质前体细胞中的？-catenin可促进软骨细胞分化，并阻断Wnt14在关节形成中的活性。在早期分化的软骨细胞中异位表达活化形式的β-连环蛋白或WNT14诱导了异位关节的形成，这是由形态和基因表达谱所定义的。相反，软骨细胞中？-连环蛋白的基因去除导致了关节融合。这些结果表明，Wnt/？-catenin信号通路是诱导滑膜关节早期形成的必要条件和充分条件。

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 signaling components are either inactivated or ectopically expressed, 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.In addition, we have found that several Wnt genes are expressed in overlapping and complementary patterns in the developing synovial joints, where ?-catenin protein levels and transcription activity were up-regulated. Removal of ?-catenin early in mesenchymal progenitor cells promoted chondrocyte differentiation and blocked the activity of Wnt14 in joint formation. Ectopic expression of an activated form of ?-catenin or Wnt14 in early differentiating chondrocytes induced ectopic joint formation defined by morphology and gene expression profile. In contrast, genetic removal of ?-catenin in chondrocytes led to joint fusion. These results demonstrate that the Wnt/ ?-catenin signaling pathway is both necessary and sufficient to induce early steps of synovial joint formation.