Abstract
We have carried out a small pool expression screen for modulators of the Wnt/beta-catenin pathway and identified Xenopus R-spondin2 (Rspo2) as a secreted activator of this cascade. Rspo2 is coexpressed with and positively regulated by Wnt signals and synergizes with Wnts to activate beta-catenin. Analyses of functional interaction with components of the Wnt/beta-catenin pathway suggest that Rspo2 functions extracellularly at the level of receptor ligand interaction. In addition to activating the Wnt/beta-catenin pathway, Rspo2 overexpression blocks Activin, Nodal, and BMP4 signaling in Xenopus, raising the possibility that it may negatively regulate the TGF-beta pathway. Antisense Morpholino experiments in Xenopus embryos and RNAi experiments in HeLa cells reveal that Rspo2 is required for Wnt/beta-catenin signaling. In Xenopus embryos depleted of Rspo2, the muscle markers myoD and myf5 fail to be activated and later muscle development is impaired. Thus, Rspo2 functions in a positive feedback loop to stimulate the Wnt/beta-catenin cascade.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Blotting, Western
-
Cell Line
-
Culture Techniques / methods
-
Cytoskeletal Proteins
-
Extracellular Matrix Proteins
-
Genes, Reporter
-
HeLa Cells
-
Humans
-
Immunohistochemistry
-
In Situ Hybridization
-
Intercellular Signaling Peptides and Proteins
-
Luciferases / metabolism
-
Microinjections
-
Molecular Sequence Data
-
Muscle Development*
-
Neoplasm Proteins / chemistry
-
Neoplasm Proteins / metabolism*
-
Proto-Oncogene Proteins / metabolism*
-
RNA / biosynthesis
-
RNA, Small Interfering / metabolism
-
Recombinant Proteins / metabolism
-
Signal Transduction*
-
Trans-Activators
-
Wnt Proteins
-
Xenopus / embryology*
-
Xenopus / genetics
-
Xenopus Proteins / chemistry
-
Xenopus Proteins / metabolism*
-
beta Catenin
Substances
-
CTNNB1 protein, Xenopus
-
CTNNB1 protein, human
-
Cytoskeletal Proteins
-
Extracellular Matrix Proteins
-
Intercellular Signaling Peptides and Proteins
-
Neoplasm Proteins
-
Proto-Oncogene Proteins
-
RNA, Small Interfering
-
Recombinant Proteins
-
Rspo2 protein, Xenopus
-
SPON2 protein, human
-
Trans-Activators
-
Wnt Proteins
-
Xenopus Proteins
-
beta Catenin
-
RNA
-
Luciferases
Associated data
-
GENBANK/AY753198
-
GENBANK/AY753199