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

• Daniel Perea ^[2] ; Jordi Guiu ^[1] ; Bruno Hudry ^[2] ; Chrysoula Konstantinidou ^[2] ; Alexandra Milona ^[2] ; Dafni Hadjieconomou ^[2] ; Thomas Carroll ^[2] ; Nina Hoyer ^[3] ; Dipa Natarajan ^[4] ; Jukka Kallijärvi ^[5] ; James A Walker ^[6] ; Peter Soba ^[3] ; Nikhil Thapar ^[4] ; Alan J Burns ^[4] ; Kim B Jensen ^[1] ; Irene Miguel‐Aliaga ^[2]
  1. [1] University of Copenhagen

     University of Copenhagen

     Dinamarca

     
  2. [2] Imperial College London

     Imperial College London

     Reino Unido

     
  3. [3] 3 Center for Molecular Neurobiology University Medical Center Hamburg‐Eppendorf (UKE) University of Hamburg Hamburg Germany
  4. [4] 4 Stem Cells and Regenerative Medicine UCL Institute of Child Health London UK
  5. [5] 5 Institute of Biotechnology University of Helsinki Helsinki Finland; 8Present address: Folkhälsan Research Center Helsinki Finland
  6. [6] 6 Center for Human Genetic Research Massachusetts General Hospital and Harvard Medical School Boston MA USA

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 36, Nº. 20, 2017, págs. 3029-3045
• Idioma: inglés
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• Resumen

  • 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.