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: 6681686
• 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/6681686
• 关键词: biological signal transduction; bone development; cell proliferation; chondrocytes; developmental genetics; histogenesis; laboratory mouse; limbs; osteoblasts; parathyroid hormone related protein; skeletal system; tissue /cell culture; vertebrate embryology

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.

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家族成员的信号分子决定了晚期结构（即骨骼元素）形成的位置和时间。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）首先从间充质凝聚分化。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hedgehog信号成分失活或异位表达的突变小鼠，我们发现在Wnt家族中，Wnt5a与印度刺猬（Ihh）和甲状旁腺激素相关肽平行，是从增殖软骨细胞过渡到前肥大软骨细胞所必需的。（PTHrP）。此外，我们还发现，重要的细胞周期调控因子如Cyclin D1和p130，视网膜母细胞瘤家族的成员，表现出互补的表达模式，与软骨细胞区的不同增殖和分化状态相关。此外，我们发现，Wnt5a和Wnt5b出现协调软骨细胞增殖和分化的差异调节细胞周期蛋白D1和p130的表达，以及软骨细胞特异性ColII的表达。我们的数据表明，Wnt5a和Wnt5b控制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Wnt 5a在调控胚胎发育中的信号转导机制以及与其他信号通路的相互作用。我们已经发现，Wnt5a，与许多其他Wnt相反，通过一种新的途径来拮抗经典的Wnt途径来调节胚胎发育，并可能抑制肿瘤形成。