Casein kinase 1‐epsilon or 1‐delta required for Wnt‐mediated intestinal stem cell maintenance. (28th September 2017)

• Record Type: Journal Article
• Authors: Morgenstern, Yael; Das Adhikari, Upasana; Ayyash, Muneef; Elyada, Ela; Tóth, Beáta; Moor, Andreas; Itzkovitz, Shalev; Ben‐Neriah, Yinon
• Is Part Of: EMBO journal. Volume 36:Number 20(2017)
• Page Start: 3046
• Page End: 3061
• Publication Date: 2017-09-28
• Subjects: adult stem cells -- casein kinase I -- intestine stem cells -- LGR5 -- Wnt; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201696253
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. Synopsis: Casein kinase 1 (CKI) isoforms CKIδ and CKIε facilitate Wnt‐mediated intestinal homeostasis and stem cell survival. Combined deletion of CKIδ/ε in the mouse intestine induces tissue atrophy and cell‐cycle arrest in p53‐independent manner. Combined deletion of CKIδ/ε in Lgr5 + intestinal stem cells (ISCs) compromises self‐renewal, leading to Wnt inhibition and apoptosis. Wnt suppression in ISCs is associated with reduced levels of nuclear Dvl and Fzd7 expression. Exogenous expression of nuclear Dvl rescues CKIδ/ε ‐deleted organoids, which resume Fzd7 and Lgr5 expression. Abstract : Casein kinase isoforms CKIδ and CKIε facilitate Wnt‐mediated intestinal homeostasis and stem cell survival.