Wnt signaling in vetebrate limb and skeletal development

细胞-细胞信号传导是脊椎动物胚胎控制其发育的主要策略。我们对wnt介导的主要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机制理解很感兴趣。在肢体发育的早期，包括Wnt家族成员在内的信号分子决定了晚期结构，即骨骼元件将在何时何地形成。肢体的骨骼形态发生是通过软骨内成骨发生的，其中软骨细胞（形成软骨）和成骨细胞（分泌骨基质）从间充质凝聚中分化出来。随后是软骨细胞和成骨细胞的顺序增殖和成熟，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。在过去的一年中，我们发现(1)PTHrP信号在调节软骨细胞肥大中作用于Wnt信号的下游。Wnt信号独立于PTHrP信号调节肥大软骨细胞的最终成熟；(2)在正常发育和疾病中，通过G蛋白介导的信号传导在调节Wnt信号活动中发挥重要作用；(3) Wnt/PCP通路对骨骼形态发生至关重要。在与Bodine博士的合作中，我们还发现骨髓微环境中的Wnt/ β -连环蛋白信号对于长期维持造血祖细胞是必需的。

Cell-cell signaling is a major strategy that vertebrate embryos employ to control their development. We are interested in the mechanistic understanding of a major signaling pathway mediated by Wnts in the control of vertebrate embryonic development, in particular, limb development and skeletal morphogeneis. Early in limb development, signaling molecules which include the Wnt 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. In the past year, we have found that (1) PTHrP signaling acts downstream of Wnt signlaing in regulating chondrocyte hypetrophy. and that Wnt signlaing regulates the final maturation of hypertrophic chondrocytes independently of PTHrP signaling; (2) Signaling through G proteins play important roles to modulate Wnt signaling activities both in normal development and in diseases; (3) The Wnt/PCP pathway is critical for skeletal morphogenesis. In collaboration with Dr. Bodine, we also found that Wnt/beta catenin signaling in the bone marrow microenviroment is required for long-term maintenance of hematopoietic progenitors.