Description
R-Spondin 1 (RSPO1, roof plate-specific spondin1), also called cysteine-rich and single thrombospondin domain containing-3 (Cristin 3), is a 27kD secreted protein that shares ~40% amino acid identity with the other three R-Spondin family members (1, 2). All are positive modulators of Wnt/b-catenin signaling, but each has a distinct expression pattern (1-3). Like other R-spondins, R-Spondin1 contains two adjacent cysteine-rich furin-like domais (aa34-135) with one potential N-glycosylation site (aa36), followed by a thrombospondin (TSP-1) motif (aa147-207) and a region rich in basic residues (aa211-263). Only the furin-like domains are needed for b-catenin stabilization (2,4). A putative nuclear localization signal at the C-terminus may allow some expression in the nucleus (5). Potential isoforms of 200 and 236aa have an alternate, shorter N-terminus or are missing aa146-208, respectively (6). Over aa21-263, human R-Spondin 1 shares 89%, 87%, 92%, 91%, 91% and 89% aa identity with mouse, rat, equine, canine, caprine and bovine RSPO-1, respectively. R-Spondin 1 is expressed in early development a 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 (7,8). Disruption is also associated with palmoplantar keratosis (7,8). Postnatally, R-Spondin 1 is expressed by neuroendocrine cells in the intestine, adrenal gland and pancreas, and by epithelia in kidney and prostate (9). Injection of recombinant R-Spondin 1 in mice causes activation of b-catenin and proliferation of intestinal crypt epithelial cells, and ameliorates experimental colitis (9,10). R-Spondin 1 regulates Wnt/b-catenin by competing with the Wnt antagonist DKK-1 for binding to the Wnt co-receptors, Kremen and LRP-6, reducing their DKK-1-mediated internalization (11). Reports differ on whether R-Spondin 1 binds LRP-6 directly (11-13)