Wnt and Hedgehog signaling in vetebrate limb and skeleta

脊椎动物肢体和骨骼中的 Wnt 和 Hedgehog 信号传导

• 批准号: 7147960
• 负责人: Yingzi Yang
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7147960
• 关键词: Wnt; Hedgehog; signaling; vetebrate; limb

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 beta-catenin protein levels and transcription activity were up-regulated. We demonstrated that that Wnt/ beta-catenin signaling pathway is both necessary and sufficient to induce early steps of synovial joint formation. Furthermore, we found that the Wnt/ beta-catenin signaling pathway also controls the differentiation of osteoblasts and chondrocytes from mesenchymal progenitor cells. Wnt/ beta-catenin signaling pathway is also essential in the regulation of chondrocyte hypertrophy. Our results indicate that by manupilating the strength of the Wnt/ beta-catenin signaling, it is now possible to direct the differentiation of progenitor cells and stem cells along only the chondrocyte or osteoblast lineage. Our research work demonstrated that the Wnt/ beta-catenin signaling pathway is a critical target for the therapeutic development of both osteoporosis and osteoarthritis.

在脊椎动物胚胎发育的早期，细胞间信号传导起着重要作用。我们感兴趣的是Wnt和hedgehog信号通路在脊椎动物胚胎发育控制中的机制，特别是肢体发育和骨骼形态发生。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后期结构（即骨骼元件）形成的地点和时间。肢体中的骨骼形态发生是通过软骨内骨形成发生的，其中软骨细胞（它们形成软骨）和成骨细胞（它们分泌骨基质）首先从间充质凝结中分化出来。接下来是软骨细胞和成骨细胞的连续增殖和成熟，它们受到严格调节和协调，以确保骨骼系统的正确形态发生。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经典 Wnt 通路，从而调节胚胎发育，并可能抑制肿瘤形成。此外，我们还发现一些 Wnt 基因在发育中的滑膜中以重叠和互补的模式表达。 关节中，β-连环蛋白水平和转录活性上调。我们证明 Wnt/β-连环蛋白信号通路对于诱导滑膜关节形成的早期步骤是必要且充分的。此外，我们发现Wnt/β-连环蛋白信号通路还控制间充质祖细胞向成骨细胞和软骨细胞的分化。 Wnt/β-catenin信号通路在软骨细胞肥大的调节中也至关重要。我们的结果表明，通过操纵 Wnt/β-连环蛋白信号的强度，现在可以指导祖细胞和干细胞仅沿着软骨细胞或成骨细胞谱系分化。我们的研究工作表明，Wnt/β-连环蛋白信号通路是骨质疏松症和骨关节炎治疗发展的关键靶点。