Wnt and Hedgehog signaling in vetebrate limb and skeleta

细胞间信号传导在脊椎动物胚胎发育中发挥着重要作用。我们感兴趣的是在脊椎动物胚胎发育，特别是肢体发育和骨骼形态发生的控制Wnt和刺猬信号通路的机制的理解。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，骨架元素就会形成。肢体中的骨骼形态发生通过软骨内骨形成发生，其中软骨细胞（它们形成软骨）和成骨细胞（它们分泌骨基质）从间充质凝聚分化。随后是软骨细胞和成骨细胞的连续增殖和成熟，它们受到严格的调节和协调，以确保骨骼系统的正确形态发生。通过分析Wnt和Hh信号成分失活或异位表达的突变小鼠，我们发现了Ihh信号在滑膜关节形成中的作用以及Wnt/β-连环蛋白信号在调节软骨细胞存活中的重要功能。更重要的是，我们发现Wnt和Ihh信号以不同的方式相互作用，以控制成骨细胞分化、软骨细胞增殖、肥大、存活和发育中的软骨内骨中的滑膜关节形成。β-连环蛋白是成骨细胞分化所需的Ihh信号传导和Osterix表达的下游。但在软骨细胞存活中，β-连环蛋白是Ihh信号上游所必需的，以抑制软骨细胞凋亡。此外，Ihh信号可以独立于β-连环蛋白抑制软骨细胞肥大和滑膜关节形成。然而，Wnt/β-catenin和Ihh信号转导在调节滑膜关节形成中存在强烈的协同相互作用。

Cell-cell signaling plays important roles in vertebrate embryonic development. 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 determine where and when the late structures, i.e., 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 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 Hh signaling components are either inactivated or ectopically expressed, we have uncovered previously unexpected roles of Ihh signaling in synovial joint formation and the essential function of Wnt/beta-catenin signaling in regulating chondrocyte survival. More importantly, we found that Wnt and Ihh signaling interact with each other in distinct ways to control osteoblast differentiation, chondrocyte proliferation, hypertrophy, survival and synovial joint formation in the developing endochondral bone. Beta-catenin is required downstream of Ihh signaling and Osterix expression for osteoblast differentiation. But in chondrocyte survival, beta-catenin is required upstream of Ihh signaling to inhibit chondrocyte apoptosis. In addition, Ihh signaling can inhibit chondrocyte hypertrophy and synovial joint formation independently of beta-catenin. However, there is a strong synergistic interaction between Wnt/beta-catenin and Ihh signaling in regulating synovial joint formation.