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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; ... Miguel-Aliaga, I; + view all (2017) Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia. The EMBO Journal , 36 (18) , Article e201696247. 10.15252/embj.201696247. Green open access

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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.

Type: Article
Title: Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/embj.201696247
Publisher version: http://dx.doi.org/10.15252/embj.201696247
Language: English
Additional information: © 2017 The Authors. Published under the terms of the CC BY 4.0 license
Keywords: Drosophila, Ret, enteroendocrine, intestine, stem cell
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1574483
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