Casein kinase 1-epsilonor1-delta required for Wnt-mediated intestinal stem cell maintenance

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, CKI epsilon, which is specifically upregulated in ISCs and is essential for ISC maintenance, especially in the absence of its close isoform CKI delta. Co-ablation of CKI delta/epsilon 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 CKI delta/epsilon-deficient enterocyte populations, with the exception of Lgr5(+) ISCs, which exhibit Dvl2-dependent Wnt signaling attenuation. CKI delta/epsilon-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.