Phospho-regulation of ATOH1 Is Required for Plasticity of Secretory Progenitors and Tissue Regeneration.

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 remains unknown. Here we show that phosphorylation of the transcription factor ATOH1 is required both for the contribution of secretory progenitors to the stem cell pool and for a robust regenerative response. 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 impacts overall regeneration. Progenitor plasticity maintains robust self-renewal in the intestinal epithelium and the balance between stem and progenitor fate is directly co-ordinated by ATOH1 multisite phosphorylation.