The long-term objective of the proposal is to understand the fundamental role of the cilium and the microtubule (MT)-based cytoskeleton in bone formation. It is proposed to study how the MT cytoskeleton is regulated by three signaling pathways: Wnt/ β-catenin, bone morphogenetic protein (BMP) and Shh. Wnt is known to enhance osteoblast differentiation, and several of the Wnt proteins, including Wnt6, have been shown to alter bone size. It was suggested that this role is mediated by the Wnt/β-catenin signaling pathway. Wnt6 binds to β-catenin, which translocates into the nucleus and regulates osteogenic transcription factors. The role of β-catenin in osteoblast differentiation and bone formation was demonstrated by β-catenin knock-out mouse studies and mutation analyses of human patients with β-catenin syndrome who have an abnormality in bone formation. However, how β-catenin acts is still largely unknown. We will test the hypothesis that cilium is a target of Wntβ-catenin pathway by investigating the interaction between β-catenin and the MT cytoskeleton in osteoblast. We also propose to study the relationship between BMPs, the role of cilium in their signaling pathway, and will investigate the mechanism by which Shh promotes osteoblast differentiation. The results will not only help us understand the molecular mechanism of osteogenesis but also will contribute to develop novel strategies for preventing and treating bone disease such as osteoporosis. [unreadable] [unreadable] [unreadable] [unreadable]