Non-canonical Wnt/PCP signalling regulates intestinal stem cell lineage priming towards enteroendocrine and Paneth cell fates

Nat Cell Biol. 2021 Jan;23(1):23-31. doi: 10.1038/s41556-020-00617-2. Epub 2021 Jan 4.


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 hierarchy1-6 and segregation7-12 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 progenitors7-12. 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 cells7. Finally, Wnt/PCP-activated Lgr5+ ISCs are molecularly indistinguishable from Wnt/β-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage*
  • Cell Polarity*
  • Cell Self Renewal
  • Enteroendocrine Cells / cytology*
  • Enteroendocrine Cells / metabolism
  • Female
  • Gene Expression Profiling
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Paneth Cells / cytology*
  • Paneth Cells / metabolism
  • Receptors, G-Protein-Coupled / physiology
  • Single-Cell Analysis
  • Stem Cells / cytology*
  • Stem Cells / metabolism
  • Wnt Proteins / metabolism*
  • beta Catenin / metabolism


  • CTNNB1 protein, mouse
  • Lgr5 protein, mouse
  • Receptors, G-Protein-Coupled
  • Wnt Proteins
  • beta Catenin