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Boettcher, Anika; Buettner, Maren; Tritschler, Sophie; Sterr, Michael; Aliluev, Alexandra; Oppenlaender, Lena; Burtscher, Ingo; Sass, Steffen; Irmler, Martin; Beckers, Johannes; Ziegenhain, Christoph; Enard, Wolfgang; Schamberger, Andrea C.; Verhamme, Fien M.; Eickelberg, Oliver; Theis, Fabian J. and Lickert, Heiko (2021): Non-canonical Wnt/PCP signalling regulates intestinal stem cell lineage priming towards enteroendocrine and Paneth cell fates. In: Nature Cell Biology, Vol. 23, No. 1

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Polarity cues regulate intestinal stem cell fate. Bottcher et al. demonstrate that mouse intestinal stem cells, which express the Wnt/planar cell polarity reporter Flattop, are primed either towards the enteroendocrine or Paneth cell lineage. A detailed understanding of intestinal stem cell (ISC) self-renewal and differentiation is required to treat chronic intestinal diseases. However, the different models of ISC lineage hierarchy(1-6) and segregation(7-12) are subject to debate. Here, we have discovered non-canonical Wnt/planar cell polarity (PCP)-activated ISCs that are primed towards the enteroendocrine or Paneth cell lineage. Strikingly, integration of time-resolved lineage labelling with single-cell gene expression analysis revealed that both lineages are directly recruited from ISCs via unipotent transition states, challenging the existence of formerly predicted bi- or multipotent secretory progenitors(7-12). Transitory cells that mature into Paneth cells are quiescent and express both stem cell and secretory lineage genes, indicating that these cells are the previously described Lgr5(+) label-retaining cells(7). Finally, Wnt/PCP-activated Lgr5(+) ISCs are molecularly indistinguishable from Wnt/beta-catenin-activated Lgr5(+) ISCs, suggesting that lineage priming and cell-cycle exit is triggered at the post-transcriptional level by polarity cues and a switch from canonical to non-canonical Wnt/PCP signalling. Taken together, we redefine the mechanisms underlying ISC lineage hierarchy and identify the Wnt/PCP pathway as a new niche signal preceding lateral inhibition in ISC lineage priming and segregation.

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