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

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Title: Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia.
Authors: Perea, D
Guiu, J
Hudry, B
Konstantinidou, C
Milona, A
Hadjieconomou, D
Carroll, T
Hoyer, N
Natarajan, D
Kallijärvi, J
Walker, JA
Soba, P
Thapar, N
Burns, AJ
Jensen, KB
Miguel-Aliaga, I
Item 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.
Issue Date: 12-Sep-2017
Date of Acceptance: 28-Jul-2017
URI: http://hdl.handle.net/10044/1/51967
DOI: https://dx.doi.org/10.15252/embj.201696247
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
Keywords: Drosophila
Ret
enteroendocrine
intestine
stem cell
06 Biological Sciences
08 Information And Computing Sciences
11 Medical And Health Sciences
Developmental Biology
Publication Status: Published online
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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