R-spondins are BMP receptor antagonists in Xenopus early embryonic development

Lee, Hye-Yoon; Seidl, Carina; Sun, Rui; Glinka, Andrey; Niehrs, Christof

doi:10.1038/s41467-020-19373-w

Cited by 44 publications

(75 citation statements)

References 64 publications

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“…Although there is an apparent paradox in that both Rspo3 and its deletion increase -catenindependent signaling, these results can in fact be explained. Our data and that of others 23 suggest that there are alternate Rspo3-mediated signaling mechanisms, separate from the Fzd/Lrp/-catenin Wnt pathway, including the Wnt/PCP signaling 14,15 and that these events can in turn regulate Wnt signaling intra-cellularly. Indeed, -catenin can be stabilized independent of the proximal activation of the canonical Wnt signaling machinery through changes in other signaling pathways 3,48,50 .…”

Section: Discussionsupporting

confidence: 74%

“…Supporting the fact that Rspo3 can also regulate Wnt-independent pathways, a recent study has suggested that Rspo3 acts as an antagonist to BMPR1A, inhibiting BMP signaling during development 23 . Thus, our observations may be due, at least in part, to changes (activation) in BMP signaling, which in turn could lead to the observed increase in pErk 44 .…”

Section: Discussionmentioning

confidence: 97%

“…Since both Rspo3 haplo-insufficiency and its deletion lead to -catenin stabilization, we then asked whether, possibly in addition to or explaining the decreased efficacy of Dkk1, Rspo3 might also be involved in the regulation of other signaling pathways which in turn can stabilize -catenin, stimulating osteoblastogenesis and counteracting Dkk1 efficacy. It has been proposed that Rspo3 binding to Lgr4 inhibits Erk phosphorylation (pErk) 23,40,44 . We therefore investigated Erk signaling, known to activate Wnt signaling and to regulate OB differentiation and bone mass [45][46][47][48] , in our model.…”

Section: Rspo3 Haplo-insufficiency and Deletion Impair Dkk1-wnt Inhibitory Activitymentioning

confidence: 99%

“…Additionally, it has been shown that Rspos can potentiate non-canonical Wnt cascades, such as the Wnt/PCP signaling 14,15 and can function as antagonists of BMPR1 in Xenopus 23 , two events that could have a negative impact on bone formation and bone mass. Thus, the mechanisms involved in the Rspos/Wnt signaling axis and their influence on skeletal homeostasis appear be more complex in vivo.…”

Section: Introductionmentioning

confidence: 99%

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

Nagano

Yamana

Saito

et al. 2021

Preprint

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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.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 97%

Section: Rspo3 Haplo-insufficiency and Deletion Impair Dkk1-wnt Inhibitory Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Nagano

Yamana

Saito

et al. 2021

Preprint

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“…In ESRD, serum sclerostin is associated with vascular calci cation and predicts coronary and epigastric artery calci cation 33 . R-spondin (RSPO) proteins are agonists of Wnt/β-catenin signaling 34 and attenuate DKK1-associated inhibition of the Wnt-pathway 12,35,36 . Moreover, RSPO stimulates Wntdependent stem cells to maintain tissue homeostasis 37 .…”

Section: Introductionmentioning

confidence: 99%

Wnt/β-catenin pathway proteins in end-stage renal disease

Al‐Hakeim

Asad

Maes

2021

Preprint

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Background. Wnt-pathway proteins play a vital role in kidney development and defects in the Wnt-pathway are associated with kidney disorders. However, the knowledge on the role of Wnt/β-catenin pathway proteins in end-stage renal disease (ESRD) is limited.Aim of the study. To delineate the association of ESRD and Wnt-proteins including the agonistR-spondin 1, the transducer β-catenin and the antagonists Dickkopf-related protein 1 (DKK1) and sclerostin.Methods. Serum Wnt-pathway proteins levels were measured by ELISA, while other biochemicals were measured spectrophotometrically in 60 ESRD patients and 30 normal controls.Results. DKK1 and sclerostin were significantly higher in ESRD than in controls, and β-catenin and the catenin + R-Sponin-1 / DKK1 + sclerostin ratio, reflecting the ratio of agonist and transducer / antagonists (AT/ANTA), were significantly lower in ESRD. Logistic regression analysis showed that ESRD was significantly predicted by increased levels of DDK1 and sclerostin and lowered β-catenin (p<0.001). eGFR was significantly associated with DKK1 and sclerostin (inversely), β-catenin (positively) and the AT/ANTA ratio (r=0.468, p<0.001). DKK1 levels were significantly and positively correlated with urea, creatinine, and copper. DKK1 and sclerostin were inversely associated with hemoglobin and packet cell volume. Catenin was significantly negatively associated with copper, urea and creatinine.Conclusion. Wnt/β-catenin pathway proteins show significant alterations in ESRD, indicating significantly increased levels of antagonists and, therefore, attenuated Wnt/β-catenin pathway activity. The latter is associated with lowered eGFR and increased serum copper levels. Wnt/β-catenin pathway proteins are possible drug targets to treat ESRD or its consequences.

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Investigating the Interactions of Glioma Stem Cells in the Perivascular Niche at Single‐Cell Resolution using a Microfluidic Tumor Microenvironment Model

et al. 2022

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The perivascular niche (PVN) is a glioblastoma tumor microenvironment (TME) that serves as a safe haven for glioma stem cells (GSCs), and acts as a reservoir that inevitably leads to tumor recurrence. Understanding cellular interactions in the PVN that drive GSC treatment resistance and stemness is crucial to develop lasting therapies for glioblastoma. The limitations of in vivo models and in vitro assays have led to critical knowledge gaps regarding the influence of various cell types in the PVN on GSCs behavior. This study developed an organotypic triculture microfluidic model as a means to recapitulate the PVN and study its impact on GSCs. This triculture platform, comprised of endothelial cells (ECs), astrocytes, and GSCs, is used to investigate GSC invasion, proliferation and stemness. Both ECs and astrocytes significantly increased invasiveness of GSCs. This study futher identified 15 ligand‐receptor pairs using single‐cell RNAseq with putative chemotactic mechanisms of GSCs, where the receptor is up‐regulated in GSCs and the diffusible ligand is expressed in either astrocytes or ECs. Notably, the ligand–receptor pair SAA1‐FPR1 is demonstrated to be involved in chemotactic invasion of GSCs toward PVN. The novel triculture platform presented herein can be used for therapeutic development and discovery of molecular mechanisms driving GSC biology.

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R-spondins are BMP receptor antagonists in Xenopus early embryonic development

Cited by 44 publications

References 64 publications

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

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

Wnt/β-catenin pathway proteins in end-stage renal disease

Investigating the Interactions of Glioma Stem Cells in the Perivascular Niche at Single‐Cell Resolution using a Microfluidic Tumor Microenvironment Model

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