Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia
Perea D, Guiu J, Hudry B, Konstantinidou C, Milona A, Hadjieconomou D, Carroll T, Hoyer N, Natarajan D, Kallijarvi J, Walker JA, Soba P, Thapar N, Burns AJ, Jensen KB, Miguel-Aliaga I (2017)
Publication Type: Journal article
Publication year: 2017
Journal
Book Volume: 36
Pages Range: 3029-3045
Journal Issue: 20
Abstract
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.
Authors with CRIS profile
Involved external institutions
Imperial College London / The Imperial College of Science, Technology and Medicine
United Kingdom (GB)
University of Copenhagen
Denmark (DK)
Universität Hamburg (UHH)
Germany (DE)
University College London (UCL)
United Kingdom (GB)
Helsingin yliopisto / University of Helsinki
Finland (FI)
Massachusetts General Hospital
United States (USA) (US)
United Kingdom (GB)
University of Copenhagen
Denmark (DK)
Universität Hamburg (UHH)
Germany (DE)
University College London (UCL)
United Kingdom (GB)
Helsingin yliopisto / University of Helsinki
Finland (FI)
Massachusetts General Hospital
United States (USA) (US)
How to cite
APA:
Perea, D., Guiu, J., Hudry, B., Konstantinidou, C., Milona, A., Hadjieconomou, D.,... Miguel-Aliaga, I. (2017). Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia. EMBO Journal, 36(20), 3029-3045. https://doi.org/10.15252/embj.201696247
MLA:
Perea, Daniel, et al. "Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia." EMBO Journal 36.20 (2017): 3029-3045.
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