TY - JOUR
T1 - The pan-ErbB negative regulator lrig1 is an intestinal stem cell marker that functions as a tumor suppressor
AU - Powell, Anne E.
AU - Wang, Yang
AU - Li, Yina
AU - Poulin, Emily J.
AU - Means, Anna L.
AU - Washington, Mary K.
AU - Higginbotham, James N.
AU - Juchheim, Alwin
AU - Prasad, Nripesh
AU - Levy, Shawn E.
AU - Guo, Yan
AU - Shyr, Yu
AU - Aronow, Bruce J.
AU - Haigis, Kevin M.
AU - Franklin, Jeffrey L.
AU - Coffey, Robert J.
N1 - Funding Information:
A.E.P., Y.W., Y.L., K.M.H., J.L.F. and R.J.C. designed, executed and analyzed data. E.J.P., J.N.H., and A.J. provided technical assistance. S.E.L. conducted the RNA-Seq. A.L.M., M.K.W., N.P., Y.G., Y.S., and B.J.A. provided expert analysis. A.E.P. and R.J.C. assembled the manuscript. We thank Frank Revetta and Catherine Meador for technical assistance and Robert Whitehead for guidance. This work was supported by the National Cancer Institute CA151566 to R.J.C. and K.M.H., and CA46413, MMHCC U01CA084239, and Gastrointestinal Specialized Program of Research Excellence P50CA095103 to R.J.C., T32GM008554 to E.J.P. and T32CA119925 to A.E.P. The authors acknowledge the support of Vanderbilt's Clinical and Translational Science Award and Transgenic Mouse/ES Cell, Cell Imaging, and Flow Cytometry Shared Resources. We thank the Peter Powell and Mary Catherine Mundell Coffey Memorial Gastrointestinal Cancer Fund for its generous support.
PY - 2012/3/30
Y1 - 2012/3/30
N2 - Lineage mapping has identified both proliferative and quiescent intestinal stem cells, but the molecular circuitry controlling stem cell quiescence is incompletely understood. By lineage mapping, we show Lrig1, a pan-ErbB inhibitor, marks predominately noncycling, long-lived stem cells that are located at the crypt base and that, upon injury, proliferate and divide to replenish damaged crypts. Transcriptome profiling of Lrig1+ colonic stem cells differs markedly from the profiling of highly proliferative, Lgr5+ colonic stem cells; genes upregulated in the Lrig1+ population include those involved in cell cycle repression and response to oxidative damage. Loss of Apc in Lrig1+ cells leads to intestinal adenomas, and genetic ablation of Lrig1 results in heightened ErbB1-3 expression and duodenal adenomas. These results shed light on the relationship between proliferative and quiescent intestinal stem cells and support a model in which intestinal stem cell quiescence is maintained by calibrated ErbB signaling with loss of a negative regulator predisposing to neoplasia.
AB - Lineage mapping has identified both proliferative and quiescent intestinal stem cells, but the molecular circuitry controlling stem cell quiescence is incompletely understood. By lineage mapping, we show Lrig1, a pan-ErbB inhibitor, marks predominately noncycling, long-lived stem cells that are located at the crypt base and that, upon injury, proliferate and divide to replenish damaged crypts. Transcriptome profiling of Lrig1+ colonic stem cells differs markedly from the profiling of highly proliferative, Lgr5+ colonic stem cells; genes upregulated in the Lrig1+ population include those involved in cell cycle repression and response to oxidative damage. Loss of Apc in Lrig1+ cells leads to intestinal adenomas, and genetic ablation of Lrig1 results in heightened ErbB1-3 expression and duodenal adenomas. These results shed light on the relationship between proliferative and quiescent intestinal stem cells and support a model in which intestinal stem cell quiescence is maintained by calibrated ErbB signaling with loss of a negative regulator predisposing to neoplasia.
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U2 - 10.1016/j.cell.2012.02.042
DO - 10.1016/j.cell.2012.02.042
M3 - Article
C2 - 22464327
AN - SCOPUS:84859196824
VL - 149
SP - 146
EP - 158
JO - Cell
JF - Cell
SN - 0092-8674
IS - 1
ER -