R-Spondin 3 (RSPO3) is also called cysteine-rich and single thrombospondin domain containing-1 (CRISTIN1), Protein with TSP type-1 repeat (PWTSR), is a member of the R-spondin protein family. R-spondins (RSPO) are a recently discovered secretory protein family with four members in human and mouse. Although all four RSPO proteins activate the canonical Wnt pathway, RSPO2 and RSPO3 are more potent than RSPO1, whereas RSPO4 is relatively inactive. RSPO-3 is expressed ubiquitously and expressed at higher level in placenta, small intestine, fetal thymus and lymph node. RSPO3 is the activator of the beta-catenin signaling cascade, leading to TCF-dependent gene activation. RSPO3 acts both in the canonical Wnt/beta-catenin-dependent pathway and in non-canonical Wnt signaling pathway, probably by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway. RSPO3 also acts as a ligand for frizzled FZD8 and LRP6 and may negatively regulate the TGF-beta pathway.