Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation.
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.
Tu
Xiaolin
X
Department of Medicine, Washington University Medical School, St. Louis, MO 63110, USA.
Joeng
Kyu Sang
KS
Nakayama
Keiichi I
KI
Nakayama
Keiko
K
Rajagopal
Jayaraj
J
Carroll
Thomas J
TJ
McMahon
Andrew P
AP
Long
Fanxin
F
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities / Q000196:embryology; D002454:Cell Differentiation; D017077:Culture Media, Conditioned; D000072261:Dishevelled Proteins; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000166:cytology; D004789:Enzyme Activation; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010006:Osteoblasts / Q000166:cytology; D010012:Osteogenesis / Q000502:physiology*; D010716:Phosphatidylinositols / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D017077:Culture Media, Conditioned; D000072261:Dishevelled Proteins; C501127:Dkk1 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010716:Phosphatidylinositols; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; C095937:Wnt7b protein, mouse; D051176:beta Catenin; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D051745:Protein Kinase C-delta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11