The intestinal epithelium holds an immense regenerative capacity mobilized by intestinal stem cells (ISCs), much of it supported by Wnt pathway activation. Several unique regulatory mechanisms ensuring optimal levels of Wnt signaling have been recognized in ISCs. Here, we identify another Wnt signaling amplifier, CKIε, which is specifically upregulated in ISCs and is essential for ISC maintenance, especially in the absence of its close isoform CKIδ. Co-ablation of CKIδ/ε in the mouse gut epithelium results in rapid ISC elimination, with subsequent growth arrest, crypt–villous shrinking, and rapid mouse death. Unexpectedly, Wnt activation is preserved in all CKIδ/ε-deficient enterocyte populations, with the exception of Lgr5+ ISCs, which exhibit Dvl2-dependent Wnt signaling attenuation. CKIδ/ε-depleted gut organoids cease proliferating and die rapidly, yet survive and resume self-renewal upon reconstitution of Dvl2 expression. Our study underscores a unique regulation mode of the Wnt pathway in ISCs, possibly providing new means of stem cell enrichment for regenerative medicine.
Bibliographical noteFunding Information:
We thank Dr. Ferdinand Camargo for providing the DVL-NLS expression plasmid. This work was supported by grants from Israel Science Foundation (ISF)-Centers of Excellence, the European Research Council within the FP-7 (294390 PICHO), the Dr. Miriam and Sheldon G, Adelson Medical Research Foundation (AMRF), and the Israel Cancer Research Fund.
© 2017 The Authors
- adult stem cells
- casein kinase I
- intestine stem cells