Phospho-regulation of ATOH1 Is Required for Plasticity of Secretory Progenitors and Tissue Regeneration.
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Authors
Tomic, Goran
Morrissey, Edward
Kozar, Sarah
Ben-Moshe, Shani
Hoyle, Alice
Azzarelli, Roberta
Kemp, Richard
Chilamakuri, Chandra Sekhar Reddy
Itzkovitz, Shalev
Winton, Douglas J
Publication Date
2018-09-06Journal Title
Cell Stem Cell
ISSN
1934-5909
Publisher
Elsevier BV
Volume
23
Issue
3
Pages
436-443.e7
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Tomic, G., Morrissey, E., Kozar, S., Ben-Moshe, S., Hoyle, A., Azzarelli, R., Kemp, R., et al. (2018). Phospho-regulation of ATOH1 Is Required for Plasticity of Secretory Progenitors and Tissue Regeneration.. Cell Stem Cell, 23 (3), 436-443.e7. https://doi.org/10.1016/j.stem.2018.07.002
Abstract
The intestinal epithelium is largely maintained by self-renewing stem cells but with apparently committed progenitors also contributing, particularly following tissue damage. However, the mechanism of, and requirement for, progenitor plasticity in mediating pathological response remain unknown. Here we show that phosphorylation of the transcription factor Atoh1 is required for both the contribution of secretory progenitors to the stem cell pool and for a robust regenerative response. As confirmed by lineage tracing, Atoh1+ cells (Atoh1(WT)CreERT2 mice) give rise to multilineage intestinal clones both in the steady state and after tissue damage. In a phosphomutant Atoh1(9S/T-A)CreERT2 line, preventing phosphorylation of ATOH1 protein acts to promote secretory differentiation and inhibit the contribution of progenitors to self-renewal. Following chemical colitis, Atoh1+ cells of Atoh1(9S/T-A)CreERT2 mice have reduced clonogenicity that affects overall regeneration. Progenitor plasticity maintains robust self-renewal in the intestinal epithelium, and the balance between stem and progenitor fate is directly coordinated by ATOH1 multisite phosphorylation.
Keywords
Intestinal Mucosa, Cell Line, Tumor, Animals, Mice, Inbred C57BL, Humans, Mice, Regeneration, Cell Differentiation, Phosphorylation, Female, Male, Basic Helix-Loop-Helix Transcription Factors
Sponsorship
Cancer Research UK
Welcome Trust
Rosetrees Trust
Stoneygate Trust
Funder references
Cancer Research UK (CB4230)
Wellcome Trust (103805/Z/14/Z)
Rosetrees Trust (A790)
Medical Research Council (MC_PC_12009)
Medical Research Council (MR/K018329/1)
Medical Research Council (MR/L021129/1)
Identifiers
External DOI: https://doi.org/10.1016/j.stem.2018.07.002
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284521
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