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: 6988870
• 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/6988870
• 关键词: biological signal transduction; bone development; cadherins; cell cell interaction; cell differentiation; cell growth regulation; cell proliferation; chondrocytes; developmental genetics; embryogenesis; genetically modified animals; histogenesis; joints; laboratory mouse; limbs; mesenchyme; osteoblasts; skeletal system; tissue /cell culture; tumor suppressor genes; 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 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.

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，以确保骨骼系统的适当形态发生。通过分析Wnt信号传导成分失活或异位表达的突变小鼠，我们发现Wnt 5a与许多其他Wnt相反，通过一种新的信号传导途径拮抗经典Wnt信号传导途径来调节胚胎发育并可能抑制肿瘤形成。此外，我们发现几种Wnt基因在发育中的滑膜关节中以重叠和互补的模式表达，在哪儿？- catenin蛋白水平和转录活性上调。移除？-间充质祖细胞中的早期连环蛋白促进软骨细胞分化并阻断Wnt 14在关节形成中的活性。异位表达的激活形式？-在早期分化的软骨细胞中的连环蛋白或Wnt 14诱导通过形态学和基因表达谱定义的异位关节形成。与此相反，基因删除？-软骨细胞中的连环蛋白导致关节融合。这些结果表明，Wnt/？-连环蛋白信号通路是诱导滑膜关节形成的早期步骤所必需的并且是充分的。