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和Hedgehog信号成分失活或异位表达的突变小鼠的分析，我们发现在Wnt家族中，Wnt5a是从增殖的软骨细胞向肥大前期的软骨细胞转化所必需的，其途径与印度刺猬(IHH)和甲状旁腺激素相关肽(PTHrP)平行。此外，我们还发现了重要的细胞周期调控因子，如视网膜母细胞瘤家族成员Cyclin D1和p130，它们的表达模式与软骨细胞区不同的增殖和分化状态相关。此外，我们发现Wnt5a和Wnt5b似乎通过差异调控Cyclin D1和p130的表达以及软骨细胞特异性ColII的表达来协调软骨细胞的增殖和分化。我们的数据表明，Wnt5a和Wnt5b控制着不同软骨细胞区之间的转换速度。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在调节胚胎发育中传递其信号和与其他信号通路的串扰的机制。我们发现，与许多其他WNT不同，WNT5a通过一种新的途径来拮抗经典的Wnt途径，从而调节胚胎发育，并可能抑制肿瘤的形成。

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.