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.
Highlights
The identification of the Ret receptor over 20 years ago, at the time enabled by its oncogenic potential when ectopically activated, spurred a flurry of research into this highly conserved transmembrane receptor with tyrosine kinase activity (Takahashi et al, 1985; Takahashi & Cooper, 1987; Ibanez, 2013)
Ret is expressed by the adult somatic progenitors of the Drosophila intestine Expression of Ret has been reported in developing neurons of many animals including Drosophila (Pachnis et al, 1993; Sugaya et al, 1 MRC London Institute of Medical Sciences, Imperial College London, London, UK 2 BRIC—Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N, Denmark 3 Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf (UKE), University of Hamburg, Hamburg, Germany 4 Stem Cells and Regenerative Medicine, UCL Institute of Child Health, London, UK 5 Institute of Biotechnology, University of Helsinki, Helsinki, Finland 6 Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA 7 The Danish Stem Cell Center (Danstem), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Prompted by our interest in the Drosophila intestine and its neurons (Cognigni et al, 2011; Lemaitre & Miguel-Aliaga, 2013), we investigated a possible conservation of Ret expression in the enteric nervous system of flies
Summary
The identification of the Ret receptor over 20 years ago, at the time enabled by its oncogenic potential when ectopically activated, spurred a flurry of research into this highly conserved transmembrane receptor with tyrosine kinase activity (Takahashi et al, 1985; Takahashi & Cooper, 1987; Ibanez, 2013). It is well established that the endogenous activity of Ret is required for the formation and/ or maintenance of a variety of cell types including neuronal, kidney, lymphoid, hematopoietic and testis germ cells (Schuchardt et al, 1994; Naughton et al, 2006; Veiga-Fernandes et al, 2007; Ibanez, 2013; Fonseca-Pereira et al, 2014). We report an unexpected and important role for Ret in a different gastrointestinal cell population: the intestinal epithelium
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