Description
RSpondin 1 (RSPO1, Roof platespecific Spondin 1), also known as cysteinerich and single thrombospondin domain containing protein 3 (Cristin 3), is a 27kD secreted protein that shares ~40% amino acid (aa) identity with three other RSpondin family members. All RSpondins regulate Wnt/bcatenin signaling, but have distinct expression patterns. Like other RSpondins, RSpondin 1 contains two adjacent cysteinerich furinlike domains (aa34135) with one potential Nglycosylation site, followed by a thrombospondin (TSP1) motif (aa147207) and a region rich in basic residues (aa211263). Only the furinlike domains are needed for bcatenin stabilization. A putative nuclear localization signal at the Cterminus may allow some expression in the nucleus. Potential isoforms of 200 and 236aa have an alternate, shorter Nterminus or are missing aa146208, respectively. Over aa21263, human RSpondin 1 shares 89%, 87%, 92%, 91%, 91% and 89% aa identity with mouse, rat, equine, canine, caprine and bovine RSPO1, respectively. RSpondin 1 is expressed in early development at the roof plate boundary and is thought to contribute to dorsal neural tube development. In humans, rare disruptions of the RSpondin 1 gene are associated with tendencies for XX sex reversal (phenotypic male) or hermaphroditism, indicating a role for RSpondin 1 in genderspecific differentiation. Disruption is also associated with palmoplantar keratosis. Postnatally, RSpondin 1 is expressed by neuroendocrine cells in the intestine, adrenal gland and pancreas, and by epithelia in kidney and prostate. Injection of recombinant RSpondin 1 in mice causes activation of bcatenin and proliferation of intestinal crypt epithelial cells, and ameliorates experimental colitis. RSpondin 1 regulates Wnt/bcatenin by competing with the Wnt antagonist DKK1 for binding to the Wnt coreceptors, Kremen and LRP6, reducing their DKK1mediated internalization. Reports differ on whether RSpondin 1 binds LRP6 directl