Wnt signaling in vetebrate limb and skeletal development

National Human Genome Research Institute

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Abstract

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.