R-Spondin 1 (RSPO1, Roof plate-specific Spondin 1), also known as cysteine-rich and single thrombospondin domain containing protein 3 (Cristin 3), is a 27 kDa secreted protein that belongs to the R-Spondin family (1, 2). R-Spondins share around 40% aa identity. All regulate Wnt/ beta ‑catenin signaling, but have distinct expression patterns (1‑3). Like other R-spondins, R-Spondin 1 contains two adjacent cysteine-rich furin-like domains (amino acids (aa) 34‑135) followed by a thrombospondin (TSP-1) motif (aa 147‑207) and a region rich in basic residues (aa 211‑263). Only the furin-like domains are needed for beta -catenin stabilization (2, 4). A putative nuclear localization signal at the C‑terminus may allow some expression in the nucleus (5). R‑Spondin 1 contains one potential N‑glycosylation site. Mouse R‑Spondin 1 shares 98%, 94%, 94%, 93%, 92% and 88% aa identity with rat, human, horse, cow, goat and dog RSPO-1, respectively, within aa 21‑209. R‑Spondin 1 is expressed in early development at the roof plate boundary and is thought to contribute to dorsal neural tube development (3, 5). In humans, rare disruptions of the R-Spondin 1 gene are associated with tendencies for XX sex reversal (phenotypic male) or hermaphroditism, indicating a role for R‑Spondin 1 in gender-specific differentiation (6, 7). Disruption is also associated with palmoplantar keratosis (6, 7). Postnatally, R-Spondin 1 is expressed by neuroendocrine cells in the intestine, adrenal gland and pancreas, and by epithelia in kidney and prostate (8). Injection of recombinant R‑Spondin 1 in mice causes activation of beta -catenin and proliferation of intestinal crypt epithelial cells, and ameliorates experimental colitis (8, 9). R‑Spondin 1 appears to regulate Wnt/ beta ‑catenin by competing with the Wnt antagonist DKK-1 for binding to the Wnt co‑receptor, Kremen (10). This competition reduces internalization of DKK‑1/LRP‑6/Kremen complexes (10). Reports differ on whether R-Spondin 1 binds LRP-6 directly (10‑12).