Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia.
File(s)
Published version
Author(s)
Type
Journal Article
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 homoeostatic contexts. They also suggest an epithelial contribution to Ret loss-of-function disorders such as Hirschsprung disease.
Date Issued
2017-09-12
Date Acceptance
2017-07-28
Citation
EMBO Journal, 2017, 36 (20), pp.3029-3045
ISSN
0261-4189
Publisher
EMBO Press
Start Page
3029
End Page
3045
Journal / Book Title
EMBO Journal
Volume
36
Issue
20
Copyright Statement
This is an open access article under the
terms of the Creative Commons Attribution 4.0
License, which permits use, distribution and reproduction
in any medium, provided the original work is
properly cited
terms of the Creative Commons Attribution 4.0
License, which permits use, distribution and reproduction
in any medium, provided the original work is
properly cited
License URL
Identifier
PII: embj.201696247
Subjects
Drosophila
Ret
enteroendocrine
intestine
stem cell
Publication Status
Published online