Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

Research output: Contribution to journalJournal articleResearchpeer-review

  • Daniel Perea
  • Jordi Guiu
  • Bruno Hudry
  • Chrysoula Konstantinidou
  • Alexandra Milona
  • Dafni Hadjieconomou
  • Thomas Carroll
  • Nina Hoyer
  • Dipa Natarajan
  • Jukka Kallijärvi
  • James A. Walker
  • Peter Soba
  • Nikhil Thapar
  • Alan J. Burns
  • Jensen, Kim Bak
  • Irene Miguel-Aliaga

Expression of the Ret receptor tyrosine kinase is a defining feature of enteric neurons. Its importance is underscored by the effects of its mutation in Hirschsprung disease, leading to absence of gut innervation and severe gastrointestinal symptoms. We report a new and physiologically significant site of Ret expression in the intestine: the intestinal epithelium. Experiments in Drosophila indicate that Ret is expressed both by enteric neurons and adult intestinal epithelial progenitors, which require Ret to sustain their proliferation. Mechanistically, Ret is engaged in a positive feedback loop with Wnt/Wingless signalling, modulated by Src and Fak kinases. We find that Ret is also expressed by the developing intestinal epithelium of mice, where its expression is maintained into the adult stage in a subset of enteroendocrine/enterochromaffin cells. Mouse organoid experiments point to an intrinsic role for Ret in promoting epithelial maturation and regulating Wnt signalling. Our findings reveal evolutionary conservation of the positive Ret/Wnt signalling feedback in both developmental and homeostatic contexts. They also suggest an epithelial contribution to Ret loss-of-function disorders such as Hirschsprung disease.

Original languageEnglish
JournalEMBO Journal
Issue number20
Pages (from-to)3029-3045
Number of pages17
Publication statusPublished - 16 Oct 2017

    Research areas

  • Drosophila, enteroendocrine, intestine, Ret, stem cell

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