Wnts produced by Osterix-expressing osteolineage cells regulate their proliferation and differentiation

Tan, Si Hui; Senarath-Yapa, Kshemendra; Chung, Michael T.; Longaker, Michael T.; Wu, Joy Y.; Nusse, Roeland

doi:10.1073/pnas.1420463111

Cited by 52 publications

(64 citation statements)

References 60 publications

(84 reference statements)

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“…As in previous tracing experiments including stem cell lineages, we used the Wnt target gene Axin2 as a marker for Wntresponding cells (21,40,41). Although the activation of Wnt/ β-catenin signaling in round spermatids has been reported using the BAT-gal and the TCF/Lef-LacZ mouse reporter lines (13,42), Wnt reporter activity in undifferentiated spermatogonia has not been described previously.…”

Section: Discussionmentioning

confidence: 99%

Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis

Takase

Nusse

2016

Proc. Natl. Acad. Sci. U.S.A.

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122

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Spermatogonial stem cells (SSCs) fuel the production of male germ cells but the mechanisms behind SSC self-renewal, proliferation, and differentiation are still poorly understood. Using the Wnt target gene Axin2 and genetic lineage-tracing experiments, we found that undifferentiated spermatogonia, comprising SSCs and transit amplifying progenitor cells, respond to Wnt/β-catenin signals. Genetic elimination of β-catenin indicates that Wnt/β-catenin signaling promotes the proliferation of these cells. Signaling is likely initiated by Wnt6, which is uniquely expressed by neighboring Sertoli cells, the only somatic cells in the seminiferous tubule that support germ cells and act as a niche for SSCs. Therefore, unlike other stem cell systems where Wnt/β-catenin signaling is implicated in self-renewal, the Wnt pathway in the testis specifically contributes to the proliferation of SSCs and progenitor cells.

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Section: Discussionmentioning

confidence: 99%

Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis

Takase

Nusse

2016

Proc. Natl. Acad. Sci. U.S.A.

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122

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“…The Wnt/b-catenin pathway is important in fracture healing and bone formation (25)(26)(27)(28)44) and can be differentially regulated by GPCRs. (29) Dkk1, an inhibitor of the Wnt pathway, is implicated in regulating bone mass, (45) fractures can induce high expression of Dkk1 mRNA within calluses during healing, and antibody blockade of Dkk1 significantly increases bone density and maximum load at fracture callus.…”

Section: Discussionmentioning

confidence: 99%

Loss of Gi G-Protein-Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing

Wang

Hsiao

Lieu

et al. 2015

Journal of Bone and Mineral Research

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G-protein-coupled receptors (GPCRs) are key regulators of skeletal homeostasis and are likely important in fracture healing. Because GPCRs can activate multiple signaling pathways simultaneously, we used targeted disruption of G i -GPCR or activation of G s -GPCR pathways to test how each pathway functions in the skeleton. We previously demonstrated that blockade of G i signaling by pertussis toxin (PTX) transgene expression in maturing osteoblastic cells enhanced cortical and trabecular bone formation and prevented agerelated bone loss in female mice. In addition, activation of G s signaling by expressing the G s -coupled engineered receptor Rs1 in maturing osteoblastic cells induced massive trabecular bone formation but cortical bone loss. Here, we test our hypothesis that the G i and G s pathways also have distinct functions in fracture repair. We applied closed, nonstabilized tibial fractures to mice in which endogenous G i signaling was inhibited by PTX, or to mice with activated G s signaling mediated by Rs1. Blockade of endogenous G i resulted in a smaller callus but increased bone formation in both young and old mice. PTX treatment decreased expression of Dkk1 and increased Lef1 mRNAs during fracture healing, suggesting a role for endogenous G i signaling in maintaining Dkk1 expression and suppressing Wnt signaling. In contrast, adult mice with activated G s signaling showed a slight increase in the initial callus size with increased callus bone formation. These results show that G i blockade and G s activation of the same osteoblastic lineage cell can induce different biological responses during fracture healing. Our findings also show that manipulating the GPCR/cAMP signaling pathway by selective timing of G s and G i -GPCR activation may be important for optimizing fracture repair.

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“…Additionally, several Wnt ligands have been identified as being expressed by BMSCs, such as Wnt2, Wnt4, Wnt5a, Wnt11, Wnt16 and various Wnt inhibitors [43]. A comprehensive investigation into Wnt expression patterns in the developing bone and its contribution to the osteolineage identified that Wnts produced by Osx-expressing cells regulated their proliferation and differentiation [145]. For detailed information on Wnt signalling in bone homeostasis, reader is directed to a review by Baron and Kneissel [10].…”

Section: Wnt Signalling In the Bone Marrow Nichementioning

confidence: 99%

Skeletal Stem Cell Niche of the Bone Marrow

Janeczek

Scarpa

Newman

et al. 2015

Tissue-Specific Stem Cell Niche

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Wnts produced by Osterix-expressing osteolineage cells regulate their proliferation and differentiation

Cited by 52 publications

References 60 publications

Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis

Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis

Loss of Gi G-Protein-Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing

Skeletal Stem Cell Niche of the Bone Marrow

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