Abstract
Wnt signaling regulates a variety of developmental processes in animals. Although the beta-catenin-dependent (canonical) pathway is known to control cell fate, a similar role for noncanonical Wnt signaling has not been established in mammals. Moreover, the intracellular cascades for noncanonical Wnt signaling remain to be elucidated. Here, we delineate a pathway in which Wnt3a signals through the Galpha(q/11) subunits of G proteins to activate phosphatidylinositol signaling and PKCdelta in the murine ST2 cells. Galpha(q/11)-PKCdelta signaling is required for Wnt3a-induced osteoblastogenesis in these cells, and PKCdelta homozygous mutant mice exhibit a deficit in embryonic bone formation. Furthermore, Wnt7b, expressed by osteogenic cells in vivo, induces osteoblast differentiation in vitro via the PKCdelta-mediated pathway; ablation of Wnt7b in skeletal progenitors results in less bone in the mouse embryo. Together, these results reveal a Wnt-dependent osteogenic mechanism, and they provide a potential target pathway for designing therapeutics to promote bone formation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Bone and Bones / abnormalities
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Bone and Bones / embryology
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Cell Differentiation
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Culture Media, Conditioned
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Dishevelled Proteins
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Embryo, Mammalian / abnormalities
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Embryo, Mammalian / cytology
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Enzyme Activation
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GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
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Gene Deletion
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Gene Expression Regulation, Developmental
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Glycoproteins / deficiency
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Glycoproteins / metabolism*
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Intercellular Signaling Peptides and Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / metabolism
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Membrane Proteins / metabolism
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Mice
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Myristoylated Alanine-Rich C Kinase Substrate
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Osteoblasts / cytology
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Osteogenesis / physiology*
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Phosphatidylinositols / metabolism
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Kinase C-delta / metabolism*
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Signal Transduction*
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Wnt Proteins / deficiency
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Wnt Proteins / genetics
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Wnt Proteins / metabolism*
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Wnt3 Protein
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Wnt3A Protein
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beta Catenin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Culture Media, Conditioned
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Dishevelled Proteins
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Dkk1 protein, mouse
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Glycoproteins
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Phosphatidylinositols
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Phosphoproteins
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Proto-Oncogene Proteins
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RNA, Messenger
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Wnt Proteins
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Wnt3 Protein
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Wnt3A Protein
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Wnt3a protein, mouse
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Wnt7b protein, mouse
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beta Catenin
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Myristoylated Alanine-Rich C Kinase Substrate
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Protein Kinase C-delta
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GTP-Binding Protein alpha Subunits, Gq-G11