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

Hyeyoon Lee; Carina Seidl; Rui Sun; Andrey Glinka; Christof Niehrs

doi:10.1038/s41467-020-19373-w

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

Nat Commun. 2020 Nov 4;11(1):5570. doi: 10.1038/s41467-020-19373-w.

Authors

Hyeyoon Lee¹, Carina Seidl¹, Rui Sun¹, Andrey Glinka¹, Christof Niehrs^{2

3}

Affiliations

¹ Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), 69120, Heidelberg, Germany.
² Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), 69120, Heidelberg, Germany. [email protected].
³ Institute of Molecular Biology (IMB), 55128, Mainz, Germany. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Morphogenetic Protein 4 / antagonists & inhibitors*
Bone Morphogenetic Protein 4 / genetics
Bone Morphogenetic Protein 4 / metabolism
Bone Morphogenetic Protein Receptors, Type I / antagonists & inhibitors*
Bone Morphogenetic Protein Receptors, Type I / genetics
Bone Morphogenetic Protein Receptors, Type I / metabolism
Cell Line, Tumor
Embryonic Development / genetics*
Gene Expression Regulation, Developmental / genetics
Humans
In Situ Hybridization
Intercellular Signaling Peptides and Proteins
Ligands
Protein Domains
Signal Transduction / genetics
Thrombospondins / genetics
Thrombospondins / metabolism*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
Wnt Proteins / metabolism
Xenopus Proteins / antagonists & inhibitors*
Xenopus Proteins / genetics
Xenopus Proteins / metabolism*
Xenopus laevis

Substances

Bone Morphogenetic Protein 4
Intercellular Signaling Peptides and Proteins
Ligands
Rspo2 protein, Xenopus
Rspo3 protein, Xenopus
Thrombospondins
Wnt Proteins
Xenopus Proteins
bmp4 protein, Xenopus
bmpr1a protein, Xenopus
Ubiquitin-Protein Ligases
Bone Morphogenetic Protein Receptors, Type I