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Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration

Goran Tomic, Edward Morrissey, Sarah Kozar, Shani Ben-Moshe, Alice Hoyle, Roberta Azzarelli, Richard Kemp, Chandra Sekhar Reddy Chilamakuri, Shalev Itzkovitz, Anna Philpott, Douglas J. Winton
doi: https://doi.org/10.1101/268607
Goran Tomic
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
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Edward Morrissey
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK
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Sarah Kozar
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
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Shani Ben-Moshe
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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Alice Hoyle
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
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Roberta Azzarelli
Department of Oncology, Hutchison/Medical Research Council (MRC) Research Centre, University of Cambridge, Cambridge CB2 0XZ, UKWellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK
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Richard Kemp
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
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Chandra Sekhar Reddy Chilamakuri
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
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Shalev Itzkovitz
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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Anna Philpott
Department of Oncology, Hutchison/Medical Research Council (MRC) Research Centre, University of Cambridge, Cambridge CB2 0XZ, UKWellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK
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  • For correspondence: doug.winton@cruk.cam.ac.uk ap113@cam.ac.uk
Douglas J. Winton
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
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  • For correspondence: doug.winton@cruk.cam.ac.uk ap113@cam.ac.uk
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SUMMARY

The intestinal epithelium is maintained by a small number of self-renewing stem cells in homeostasis. In addition committed progenitors can contribute to the functional stem cell compartment at a low level during homeostasis and substantially during regeneration following tissue damage. However the mechanism of, and requirement for, progenitor plasticity in mediating pathological response has not been demonstrated. Here we show that multisite phosphorylation of the transcription factor Atoh1 is required both for the contribution of secretory progenitors to the intestinal stem cell pool and for a robust regenerative response following damage. In lineage tracing experiments Atoh1+ cells (Atoh1(WT)CreERT2 mice) show stem cell activity by giving rise to multilineage intestinal clones both in the steady state and after tissue damage. Notably in the colonic epithelium a single generation of Atoh1+ progenitors sustains 1 in 15 stem cells. In an activating Atoh1(9S/T-A)CreERT2 line, the loss of phosphorylation sites on the Atoh1 protein promotes secretory differentiation and inhibits the contribution of these cells to self-renewal. Finally, in a chemical colitis model the Atoh1+ cells of Atoh1(9S/T-A)CreERT2 mice have reduced clonogenic capacity that impacts overall regenerative response of the epithelium. Thus progenitor plasticity plays an integral part in maintaining robust self-renewal in the intestinal epithelium and the balance between stem and progenitor fate behaviour is directly co-ordinated by Atoh1 multi-site phosphorylation.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 26, 2018.
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Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration
Goran Tomic, Edward Morrissey, Sarah Kozar, Shani Ben-Moshe, Alice Hoyle, Roberta Azzarelli, Richard Kemp, Chandra Sekhar Reddy Chilamakuri, Shalev Itzkovitz, Anna Philpott, Douglas J. Winton
bioRxiv 268607; doi: https://doi.org/10.1101/268607
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Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration
Goran Tomic, Edward Morrissey, Sarah Kozar, Shani Ben-Moshe, Alice Hoyle, Roberta Azzarelli, Richard Kemp, Chandra Sekhar Reddy Chilamakuri, Shalev Itzkovitz, Anna Philpott, Douglas J. Winton
bioRxiv 268607; doi: https://doi.org/10.1101/268607

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