Tomic, Goran;
Morrissey, Edward;
Kozar, Sarah;
Ben-Moshe, Shani;
Hoyle, Alice;
Azzarelli, Roberta;
Kemp, Richard;
... Winton, Douglas J; + view all
(2018)
Phospho-regulation of ATOH1 Is Required for Plasticity of Secretory Progenitors and Tissue Regeneration.
Cell Stem Cell
, 23
(3)
436-443.e7.
10.1016/j.stem.2018.07.002.
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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. Tomic et al. report that multisite phosphorylation of ATOH1 regulates the contribution of secretory progenitors to stem cell self-renewal in the small intestine and colon. With damage, the enhanced role of Atoh1 + progenitors in mediating tissue repair is ablated in mice expressing phosphomutant ATOH1 and overall tissue regeneration is impaired.
| Type: | Article |
|---|---|
| Title: | Phospho-regulation of ATOH1 Is Required for Plasticity of Secretory Progenitors and Tissue Regeneration |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.stem.2018.07.002 |
| Publisher version: | https://doi.org/10.1016/j.stem.2018.07.002 |
| Language: | English |
| Additional information: | © 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Atoh1, plasticity, phosphorylation, intestinal stem cell, secretory progenitor |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10189180 |
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