Noncanonical Wnt Signaling through G Protein-Linked PKCδ Activation Promotes Bone Formation

Xiaolin Tu; Kyu Sang Joeng; Keiichi I. Nakayama; Keiko Nakayama; Jayaraj Rajagopal; Thomas J Carroll; Andrew P. McMahon; Fanxin Long

doi:10.1016/j.devcel.2006.11.003

Noncanonical Wnt Signaling through G Protein-Linked PKCδ Activation Promotes Bone Formation

Xiaolin Tu, Kyu Sang Joeng, Keiichi I. Nakayama, Keiko Nakayama, Jayaraj Rajagopal, Thomas J Carroll, Andrew P. McMahon, Fanxin Long

Research output: Contribution to journal › Article › peer-review

264 Scopus citations

Abstract

Wnt signaling regulates a variety of developmental processes in animals. Although the β-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 Gα_q/11 subunits of G proteins to activate phosphatidylinositol signaling and PKCδ in the murine ST2 cells. Gα_q/11-PKCδ signaling is required for Wnt3a-induced osteoblastogenesis in these cells, and PKCδ 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 PKCδ-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.

Original language	English (US)
Pages (from-to)	113-127
Number of pages	15
Journal	Developmental cell
Volume	12
Issue number	1
DOIs	https://doi.org/10.1016/j.devcel.2006.11.003
State	Published - Jan 2007

Keywords

DEVBIO
SIGNALING

ASJC Scopus subject areas

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

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10.1016/j.devcel.2006.11.003

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title = "Noncanonical Wnt Signaling through G Protein-Linked PKCδ Activation Promotes Bone Formation",

abstract = "Wnt signaling regulates a variety of developmental processes in animals. Although the β-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 Gαq/11 subunits of G proteins to activate phosphatidylinositol signaling and PKCδ in the murine ST2 cells. Gαq/11-PKCδ signaling is required for Wnt3a-induced osteoblastogenesis in these cells, and PKCδ 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 PKCδ-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.",

keywords = "DEVBIO, SIGNALING",

author = "Xiaolin Tu and Joeng, {Kyu Sang} and Nakayama, {Keiichi I.} and Keiko Nakayama and Jayaraj Rajagopal and Thomas J Carroll and McMahon, {Andrew P.} and Fanxin Long",

note = "Funding Information: We are indebted to Drs. Xi He, Walter Koch, Christopher Niehrs, Frank McCormick, and Steve Teitelbaum for providing reagents. We thank Drs. Deborah Stumpo and Perry Blackshear (NIEHS) for sharing MARCKS −/− mouse embryos. The work was supported in part by National Institutes of Health grants R01 DK065789 (F.L.) and P01 DK056246 (A.P.M.). K.S.J. was supported by the Korea Science and Engineering Foundation. ",

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doi = "10.1016/j.devcel.2006.11.003",

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AU - Tu, Xiaolin

AU - Joeng, Kyu Sang

AU - Nakayama, Keiichi I.

AU - Nakayama, Keiko

AU - Rajagopal, Jayaraj

AU - Carroll, Thomas J

AU - McMahon, Andrew P.

AU - Long, Fanxin

N1 - Funding Information: We are indebted to Drs. Xi He, Walter Koch, Christopher Niehrs, Frank McCormick, and Steve Teitelbaum for providing reagents. We thank Drs. Deborah Stumpo and Perry Blackshear (NIEHS) for sharing MARCKS −/− mouse embryos. The work was supported in part by National Institutes of Health grants R01 DK065789 (F.L.) and P01 DK056246 (A.P.M.). K.S.J. was supported by the Korea Science and Engineering Foundation.

PY - 2007/1

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N2 - Wnt signaling regulates a variety of developmental processes in animals. Although the β-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 Gαq/11 subunits of G proteins to activate phosphatidylinositol signaling and PKCδ in the murine ST2 cells. Gαq/11-PKCδ signaling is required for Wnt3a-induced osteoblastogenesis in these cells, and PKCδ 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 PKCδ-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.

AB - Wnt signaling regulates a variety of developmental processes in animals. Although the β-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 Gαq/11 subunits of G proteins to activate phosphatidylinositol signaling and PKCδ in the murine ST2 cells. Gαq/11-PKCδ signaling is required for Wnt3a-induced osteoblastogenesis in these cells, and PKCδ 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 PKCδ-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.

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Noncanonical Wnt Signaling through G Protein-Linked PKCδ Activation Promotes Bone Formation

Abstract

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