R-spondin-1 is also known as Roof plate-specific Spondin 1 (RSPO1) and cysteinerich and single thrombospondin domain containing protein 3 (Cristin 3), is a secreted protein which belongs to the R-Spondin family and encodes a secreted activator protein with two cystein-rich, furin-like domains and one thrombospondin type 1 domain. All Rspondins regulate Wnt/β-catenin signaling, but have distinct expression patterns. Like other R-Spondins, R-Spondin-1 contains two adjacent cysteinerich furinlike domains (aa 34-135) with one potential N-glycosylation site, followed by a thrombospondin (TSP1) motif (aa 147-207) and a region rich in basic residues (aa 211-263). Only the furinlike domains are needed for β-catenin stabilization. A putative nuclear localization signal at the C-terminus may allow some expression in the nucleus. Potential isoforms of 200 and 236 aa have an alternate, shorter N-terminus or are missing aa 146-208, respectively. R-Spondin-1 is expressed in early development at the roof plate boundary and is thought to contribute to dorsal neural tube development. Human RSPO1 disruption results in a recessive syndrome characterized by XX sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin. It has been shown that the complete female-to-male sex reversal is due to the absence of the testis-determining gene, SRY. R-Spondin-1 regulates Wnt/β-catenin by competing with the Wnt antagonist DKK1 for binding to the Wnt co receptors, Kremen and LRP6, reducing their DKK1 mediated internalization. Reports differ on whether R-spondin 1 binds LRP6 directly.