R-spondins Are BMP Receptor Antagonists in Xenopus Early Embryonic Development

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Nov 5

PMID 33149137

Citations 22

Authors

Hyeyoon Lee

Carina Seidl

Rui Sun

Andrey Glinka

Christof Niehrs

Affiliations

Soon will be listed here.

Abstract

BMP signaling plays key roles in development, stem cells, adult tissue homeostasis, and disease. How BMP receptors are extracellularly modulated and in which physiological context, is therefore of prime importance. R-spondins (RSPOs) are a small family of secreted proteins that co-activate WNT signaling and function as potent stem cell effectors and oncogenes. Evidence is mounting that RSPOs act WNT-independently but how and in which physiological processes remains enigmatic. Here we show that RSPO2 and RSPO3 also act as BMP antagonists. RSPO2 is a high affinity ligand for the type I BMP receptor BMPR1A/ALK3, and it engages ZNRF3 to trigger internalization and degradation of BMPR1A. In early Xenopus embryos, Rspo2 is a negative feedback inhibitor in the BMP4 synexpression group and regulates dorsoventral axis formation. We conclude that R-spondins are bifunctional ligands, which activate WNT- and inhibit BMP signaling via ZNRF3, with implications for development and cancer.

Citing Articles

Mechanistic insights into Wnt-β-catenin pathway activation and signal transduction.

Maurice M, Angers S Nat Rev Mol Cell Biol. 2025; .

PMID: 39856369 DOI: 10.1038/s41580-024-00823-y.

[Role of R-spondin 2 on osteogenic differentiation of bone marrow mesenchymal stem cells and bone metabolism in ovariectomized mice].

Liu X, Shi B, Cai C, Wang H, Jia P Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2024; 38(11):1399-1407.

PMID: 39542634 PMC: 11563750. DOI: 10.7507/1002-1892.202406083.

Timing and Graded BMP Signalling Determines Fate of Neural Crest and Ectodermal Placode Derivatives from Pluripotent Stem Cells.

Chung K, Millet M, Rouillon L, Zine A Biomedicines. 2024; 12(10).

PMID: 39457575 PMC: 11504183. DOI: 10.3390/biomedicines12102262.

Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling.

Boonsawat P, Asadollahi R, Niedrist D, Steindl K, Begemann A, Joset P Am J Hum Genet. 2024; 111(9):1994-2011.

PMID: 39168120 PMC: 11393693. DOI: 10.1016/j.ajhg.2024.07.016.

R-Spondin 2 governs Xenopus left-right body axis formation by establishing an FGF signaling gradient.

Lee H, Camuto C, Niehrs C Nat Commun. 2024; 15(1):1003.

PMID: 38307837 PMC: 10837206. DOI: 10.1038/s41467-024-44951-7.

References

Khokha M, Yeh J, Grammer T, Harland R . Depletion of three BMP antagonists from Spemann's organizer leads to a catastrophic loss of dorsal structures. Dev Cell. 2005; 8(3):401-11. DOI: 10.1016/j.devcel.2005.01.013. View

De Robertis E, Larrain J, Oelgeschlager M, Wessely O . The establishment of Spemann's organizer and patterning of the vertebrate embryo. Nat Rev Genet. 2001; 1(3):171-81. PMC: 2291143. DOI: 10.1038/35042039. View

Zylbersztejn F, Flores-Violante M, Voeltzel T, Nicolini F, Lefort S, Maguer-Satta V . The BMP pathway: A unique tool to decode the origin and progression of leukemia. Exp Hematol. 2018; 61:36-44. DOI: 10.1016/j.exphem.2018.02.005. View

Heldin C, Moustakas A . Signaling Receptors for TGF-β Family Members. Cold Spring Harb Perspect Biol. 2016; 8(8). PMC: 4968163. DOI: 10.1101/cshperspect.a022053. View

Lebensohn A, Rohatgi R . R-spondins can potentiate WNT signaling without LGRs. Elife. 2018; 7. PMC: 5800842. DOI: 10.7554/eLife.33126. View

Fujii M, Takeda K, Imamura T, Aoki H, Sampath T, Enomoto S . Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation. Mol Biol Cell. 1999; 10(11):3801-13. PMC: 25680. DOI: 10.1091/mbc.10.11.3801. View

Chang C . Agonists and Antagonists of TGF-β Family Ligands. Cold Spring Harb Perspect Biol. 2016; 8(8). PMC: 4968162. DOI: 10.1101/cshperspect.a021923. View

Glinka A, Dolde C, Kirsch N, Huang Y, Kazanskaya O, Ingelfinger D . LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling. EMBO Rep. 2011; 12(10):1055-61. PMC: 3185347. DOI: 10.1038/embor.2011.175. View

Massague J . TGF-beta signal transduction. Annu Rev Biochem. 1998; 67:753-91. DOI: 10.1146/annurev.biochem.67.1.753. View

10.

de Lau W, Peng W, Gros P, Clevers H . The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes Dev. 2014; 28(4):305-16. PMC: 3937510. DOI: 10.1101/gad.235473.113. View

11.

Wiater E, Vale W . Inhibin is an antagonist of bone morphogenetic protein signaling. J Biol Chem. 2002; 278(10):7934-41. DOI: 10.1074/jbc.M209710200. View

12.

David C, Massague J . Contextual determinants of TGFβ action in development, immunity and cancer. Nat Rev Mol Cell Biol. 2018; 19(7):419-435. PMC: 7457231. DOI: 10.1038/s41580-018-0007-0. View

13.

Huch M, Dorrell C, Boj S, van Es J, Li V, van de Wetering M . In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature. 2013; 494(7436):247-50. PMC: 3634804. DOI: 10.1038/nature11826. View

14.

Koo B, Spit M, Jordens I, Low T, Stange D, van de Wetering M . Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 2012; 488(7413):665-9. DOI: 10.1038/nature11308. View

15.

Dal-Pra S, Furthauer M, Van-Celst J, Thisse B, Thisse C . Noggin1 and Follistatin-like2 function redundantly to Chordin to antagonize BMP activity. Dev Biol. 2006; 298(2):514-26. DOI: 10.1016/j.ydbio.2006.07.002. View

16.

Niehrs C, Pollet N . Synexpression groups in eukaryotes. Nature. 1999; 402(6761):483-7. DOI: 10.1038/990025. View

17.

Berger B, Acebron S, Herbst J, Koch S, Niehrs C . Parkinson's disease-associated receptor GPR37 is an ER chaperone for LRP6. EMBO Rep. 2017; 18(5):712-725. PMC: 5412897. DOI: 10.15252/embr.201643585. View

18.

Harland R, Gerhart J . Formation and function of Spemann's organizer. Annu Rev Cell Dev Biol. 1997; 13:611-67. DOI: 10.1146/annurev.cellbio.13.1.611. View

19.

Karaulanov E, Knochel W, Niehrs C . Transcriptional regulation of BMP4 synexpression in transgenic Xenopus. EMBO J. 2004; 23(4):844-56. PMC: 381009. DOI: 10.1038/sj.emboj.7600101. View

20.

Antebi Y, Linton J, Klumpe H, Bintu B, Gong M, Su C . Combinatorial Signal Perception in the BMP Pathway. Cell. 2017; 170(6):1184-1196.e24. PMC: 5612783. DOI: 10.1016/j.cell.2017.08.015. View