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。通过分析Wnt信号成分失活或异位表达的突变小鼠，我们发现与许多其他Wnt不同，Wnt5a通过一种新的信号通路来拮抗常规的Wnt通路，从而调节胚胎发育并可能抑制肿瘤形成。此外，我们发现几个Wnt基因在发育中的滑膜关节中以重叠和互补的模式表达，在哪里？-catenin蛋白水平和转录活性上调。移除？间充质祖细胞早期-catenin促进软骨细胞分化，阻断Wnt14在关节形成中的活性。活化形式的异位表达？-catenin或Wnt14在早期分化软骨细胞诱导异位关节形成中的作用，由形态学和基因表达谱定义。相比之下，基因去除？软骨细胞中的-catenin导致关节融合。这些结果表明Wnt/ ？-catenin信号通路在滑膜关节形成的早期阶段是必要和充分的。

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.