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Several described growth factors influence the proliferationand regeneration of the intestinal epithelium. Using a transgenicmouse model, we identified a human gene, R-spondin1, with potentand specific proliferative effects on intestinal crypt cells.Human R-spondin1 (hRSpo1) is a thrombospondin domain-containingprotein expressed in enteroendocrine cells as well as in epithelialcells in various tissues. Upon injection into mice, the proteininduced rapid onset of crypt cell proliferation involving ß-cateninstabilization, possibly by a process that is distinct from thecanonical Wnt-mediated signaling pathway. The protein also displayedefficacy in a model of chemotherapy-induced intestinal mucositisand may have therapeutic application in gastrointestinal diseases.
1 Nuvelo, Inc., 675 Almanor Avenue, Sunnyvale, CA 94085, USA. 2 Pharmaceutical Research Laboratories, Pharmaceutical Division, Kirin Brewery Co., Ltd., 3 Miyahara-cho, Takasaki-shi, Gunma 370-1295, Japan.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: wfunk{at}nuvelo.com (W.D.F.); ktomizuka{at}kirin.co.jp (K.T.)
R-Spondin Family Members Regulate the Wnt Pathway by a Common Mechanism.
K.-A. Kim, M. Wagle, K. Tran, X. Zhan, M. A. Dixon, S. Liu, D. Gros, W. Korver, S. Yonkovich, N. Tomasevic, et al. (2008)
Mol. Biol. Cell
19, 2588-2596
|Abstract »|Full Text »|PDF »
R-spondin1 plays an essential role in ovarian development through positively regulating Wnt-4 signaling.
K. Tomizuka, K. Horikoshi, R. Kitada, Y. Sugawara, Y. Iba, A. Kojima, A. Yoshitome, K. Yamawaki, M. Amagai, A. Inoue, et al. (2008)
Hum. Mol. Genet.
17, 1278-1291
|Abstract »|Full Text »|PDF »
Activation of {beta}-catenin signaling by Rspo1 controls differentiation of the mammalian ovary.
A.-A. Chassot, F. Ranc, E. P. Gregoire, H. L. Roepers-Gajadien, M. M. Taketo, G. Camerino, D. G. de Rooij, A. Schedl, and M.-C. Chaboissier (2008)
Hum. Mol. Genet.
17, 1264-1277
|Abstract »|Full Text »|PDF »
Glucagon-Like Peptide-2 Activates -Catenin Signaling in the Mouse Intestinal Crypt: Role of Insulin-Like Growth Factor-I.
P. E. Dube, K. J. Rowland, and P. L. Brubaker (2008)
Endocrinology
149, 291-301
|Abstract »|Full Text »|PDF »
The Role of Matrix Metalloproteinases in Stromal/Epithelial Interactions in the Gut.
R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6.
M. E. Binnerts, K.-A. Kim, J. M. Bright, S. M. Patel, K. Tran, M. Zhou, J. M. Leung, Y. Liu, W. E. Lomas III, M. Dixon, et al. (2007)
PNAS
104, 14700-14705
|Abstract »|Full Text »|PDF »
R-spondin1 Is a High Affinity Ligand for LRP6 and Induces LRP6 Phosphorylation and beta-Catenin Signaling.
Q. Wei, C. Yokota, M. V. Semenov, B. Doble, J. Woodgett, and X. He (2007)
J. Biol. Chem.
282, 15903-15911
|Abstract »|Full Text »|PDF »
Selection of Early-Occurring Mutations Dictates Hormone-Independent Progression in Mouse Mammary Tumor Lines.
A. Gattelli, M. N. Zimberlin, R. P. Meiss, L. H. Castilla, and E. C. Kordon (2006)
J. Virol.
80, 11409-11415
|Abstract »|Full Text »|PDF »
To whom correspondence should be addressed. E-mail: 
