scholarly journals Loss-of-function of ACVR1 in osteoblasts increases bone mass and activates canonical Wnt signaling through suppression of Wnt inhibitors SOST and DKK1

2011 ◽  
Vol 414 (2) ◽  
pp. 326-330 ◽  
Author(s):  
Nobuhiro Kamiya ◽  
Vesa M. Kaartinen ◽  
Yuji Mishina
Keyword(s):  
Bone Mass ◽  
Wnt Signaling ◽  
Loss Of Function ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt ◽  
Wnt Inhibitors

scholarly journals Reduced Affinity to and Inhibition by DKK1 Form a Common Mechanism by Which High Bone Mass-Associated Missense Mutations in LRP5 Affect Canonical Wnt Signaling

2005 ◽  
Vol 25 (12) ◽  
pp. 4946-4955 ◽  
Author(s):  
Minrong Ai ◽  
Sheri L. Holmen ◽  
Wim Van Hul ◽  
Bart O. Williams ◽  
Matthew L. Warman
Keyword(s):  
Cell Surface ◽  
Bone Mass ◽  
Wnt Signaling ◽  
Common Mechanism ◽  
Missense Mutations ◽  
Canonical Wnt Signaling ◽  
High Bone Mass ◽  
Mutant Proteins ◽  
High Bone ◽  
Canonical Wnt

ABSTRACT The low-density-lipoprotein receptor-related protein 5 (LRP5), a coreceptor in the canonical Wnt signaling pathway, has been implicated in human disorders of low and high bone mass. Loss-of-function mutations cause the autosomal recessive osteoporosis-pseudoglioma syndrome, and heterozygous missense mutations in families segregating autosomal dominant high bone mass (HBM) phenotypes have been identified. We expressed seven different HBM-LRP5 missense mutations to delineate the mechanism by which they alter Wnt signaling. None of the mutations caused activation of the receptor in the absence of ligand. Each mutant receptor was able to reach the cell surface, albeit at differing amounts, and transduce exogenously supplied Wnt1 and Wnt3a signal. All HBM mutant proteins had reduced physical interaction with and reduced inhibition by DKK1. These data suggest that HBM mutant proteins can transit to the cell surface in sufficient quantity to transduce Wnt signal and that the likely mechanism for the HBM mutations' physiologic effects is via reduced affinity to and inhibition by DKK1.

scholarly journals Canonical Wnt signaling exerts bidirectional control on choroid plexus epithelial development

2020 ◽  
Author(s):  
Arpan Parichha ◽  
Varun Suresh ◽  
Mallika Chatterjee ◽  
Aditya Kshirsagar ◽  
Lihi Ben-Reuven ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Choroid Plexus ◽  
Embryonic Stem ◽  
Mammalian Brain ◽  
Loss Of Function ◽  
Canonical Wnt Signaling ◽  
Constitutive Activation ◽  
Cortical Hem ◽  
And Function ◽  
Canonical Wnt

AbstractThe choroid plexus (CP) secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the CP epithelium (CPe) arises from the Wnt- and Bmp- expressing cortical hem. We examined the role of canonical Wnt signaling in CPe development and report that the mouse and human embryonic CPe expresses molecules in this pathway. Either loss of function or constitutive activation of β-catenin, a key mediator of canonical Wnt signaling, causes a profound disruption of mouse CPe development. Loss of β-catenin results in a dysmorphic CPe, while constitutive activation of β-catenin causes a loss of CPe identity and a transformation of this tissue to a hippocampal-like identity. Aspects of this phenomenon are recapitulated in human embryonic stem cell (hESC)-derived organoids. Our results indicate that canonical Wnt signaling is required in a precisely regulated manner for normal CP development in the mammalian brain.

scholarly journals R-spondin 3 deletion favors Erk phosphorylation to enhance Wnt signaling and bone formation

2021 ◽  
Author(s):  
Kenichi Nagano ◽  
Kei Yamana ◽  
Hiroaki Saito ◽  
Riku Kiviranta ◽  
Ana Clara Pedroni ◽  
...  
Keyword(s):  
Bone Density ◽  
Bone Formation ◽  
Bone Mass ◽  
Wnt Signaling ◽  
Erk Signaling ◽  
Canonical Wnt Signaling ◽  
Erk Phosphorylation ◽  
High Bone ◽  
Canonical Wnt

Abstract Activation of Wnt signaling leads to high bone density. The R-spondin family of four secreted glycoproteins (Rspo1-4) amplifies Wnt signaling. In humans, RSPO3 variants are strongly associated with bone density, but how RSPO3 affects skeletal homeostasis is not fully understood. Here we show that in mice Rspo3 haplo-insufficiency or its targeted deletion in osteoprogenitors lead to an increase in bone formation and bone mass. Contrary to expectations, Rspo3 haplo-insufficiency results in canonical Wnt signaling activation. Using mouse embryonic fibroblasts we show that Rspo3 deficiency leads to activation of Erk signaling, stabilizing β-catenin. Furthermore, Rspo3 haplo-insufficiency impairs Dkk1 efficacy in blocking canonical Wnt signaling and prevents the in vivo inhibition of bone formation and bone mass induced by osteoblast-targeted expression of Dkk1. We conclude that Rspo3 haplo-insufficiency/deficiency boosts canonical Wnt signaling by activating Erk signaling and impairing Dkk1’s inhibitory activity, which in turn lead to increased bone formation and bone mass.

scholarly journals R-spondin 3 deletion favors Erk phosphorylation to enhance Wnt signaling and bone formation

2021 ◽  
Author(s):  
Kenichi Nagano ◽  
Kei Yamana ◽  
Hiroaki Saito ◽  
Riku Kiviranta ◽  
Ana Clara Pedroni ◽  
...  
Keyword(s):  
Bone Density ◽  
Bone Formation ◽  
Bone Mass ◽  
Wnt Signaling ◽  
Erk Signaling ◽  
Canonical Wnt Signaling ◽  
Erk Phosphorylation ◽  
High Bone ◽  
Canonical Wnt

Abstract Activation of Wnt signaling leads to high bone density. The R-spondin family of four secreted glycoproteins (Rspo1-4) amplifies Wnt signaling. In humans, RSPO3 variants are strongly associated with bone density, but how RSPO3 affects skeletal homeostasis is not fully understood. Here we show that in mice Rspo3 haplo-insufficiency or its targeted deletion in osteoprogenitors lead to an increase in bone formation and bone mass. Contrary to expectations, Rspo3 haplo-insufficiency results in canonical Wnt signaling activation. Using mouse embryonic fibroblasts we show that Rspo3 deficiency leads to activation of Erk signaling, stabilizing β-catenin. Furthermore, Rspo3 haplo-insufficiency impairs Dkk1 efficacy in blocking canonical Wnt signaling and prevents the in vivo inhibition of bone formation and bone mass induced by osteoblast-targeted expression of Dkk1. We conclude that Rspo3 haplo-insufficiency/deficiency boosts canonical Wnt signaling by activating Erk signaling and impairing Dkk1’s inhibitory activity, which in turn lead to increased bone formation and bone mass.

scholarly journals Inhibition of phosphodiesterase 5 reduces bone mass by suppression of canonical Wnt signaling

2014 ◽  
Vol 5 (11) ◽  
pp. e1544-e1544 ◽  
Author(s):  
Y Gong ◽  
C Y Xu ◽  
J R Wang ◽  
X H Hu ◽  
D Hong ◽  
...  
Keyword(s):  
Bone Mass ◽  
Wnt Signaling ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt ◽  
Phosphodiesterase 5

DDRE-15. Sema3C SIGNALING CONFERS RESISTANCE TO Wnt INHIBITION IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi77-vi77
Author(s):  
Jing Hao ◽  
Xiangzi Han ◽  
Haidong Huang ◽  
xingjiang yu ◽  
Shideng Bao ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Wnt Pathway ◽  
Nuclear Accumulation ◽  
Tumor Control ◽  
Cell Fractionation ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt ◽  
Wnt Inhibitors

Abstract BACKGROUND Wnt signaling is widely dysregulated in cancer. The therapeutic potential of Wnt inhibitors appears promising in preclinical studies. However, they have uniformly failed clinical trials. How cancer cells develop Wnt inhibitor resistance is poorly understood. Current Wnt inhibitors are designed targeting either ligand or receptor. We hypothesized cancer cells will bypass ligand-receptor interaction through an unknown mechanism. We focused on the neurodevelopmental signaling program of Semaphorin 3C (Sema3C) that is upregulated in 85% of GBM and regulates glioma stem-cell-driven tumor progression. RESULTS Porcupine inhibitor LGK974 reduced TCF1 expression in the GBM tumor mouse models, suggesting successful target engagement in vivo. However, it failed to prolong the overall survival. Sema3C expression strongly correlated with TCF1 expression in human GBM samples by immunohistochemical analysis. Genetic inhibition of Sema3C and TCF1 together prolonged animal survival more than either alone, indicating better control of Wnt pathway signaling with dual pathway blockade. Immunofluorescence and cell fractionation studies revealed that Sema3C signaling drove β-catenin nuclear accumulation. Sema3C regulates transactivation of Wnt target genes including TCF1, c-Myc and c-Met. Sema3C pathway activates Rac1. It is reported that Rac1 activates β-catenin and promotes β-catenin nuclear accumulation. In GSCs, constitutively active Rac1 restored β-catenin nuclear localization and rescued TCF1 and c-Myc down-regulation in the setting of Sema3C silencing. Sema3C can drive canonical Wnt signaling even when Wnt ligand secretion is blocked. Together, the data support that GSCs can escape Wnt inhibition through Sema3C and Rac1. CONCLUSIONS Sema3C signaling drives canonical Wnt signaling, providing an escape mechanism for cancer cells despite Wnt ligand-receptor interruption. Sema3C-β-catenin signaling promotes GSC self-renewal and tumor progression. Upstream Wnt pathway inhibition alone is insufficient to control tumors. Our data provide a therapeutic strategy of dual blockade of Wnt and Sema3C pathways to provide clinically significant tumor control.

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