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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\n                    <jats:italic>Drosophila<\/jats:italic>\n                    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\n                    <jats:italic>Ret<\/jats:italic>\n                    loss\u2010of\u2010function disorders such as Hirschsprung disease.\n                  <\/jats:p>","DOI":"10.15252\/embj.201696247","type":"journal-article","created":{"date-parts":[[2017,9,12]],"date-time":"2017-09-12T20:10:31Z","timestamp":1505247031000},"page":"3029-3045","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia"],"prefix":"10.1038","volume":"36","author":[{"given":"Daniel","family":"Perea","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Guiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Hudry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrysoula","family":"Konstantinidou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Milona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dafni","family":"Hadjieconomou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Carroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Hoyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipa","family":"Natarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jukka","family":"Kallij\u00e4rvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Soba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikhil","family":"Thapar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan J","family":"Burns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim B","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1082-5108","authenticated-orcid":false,"given":"Irene","family":"Miguel\u2010Aliaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,9,12]]},"reference":[{"key":"BFEMBJ201696247_CR1","doi-asserted-by":"crossref","first-page":"3789","DOI":"10.1016\/j.febslet.2005.05.075","volume":"579","author":"C Abrescia","year":"2005","unstructured":"Abrescia C, Sjostrand D, Kjaer S, Ibanez CF (2005) Drosophila RET contains an active tyrosine kinase and elicits neurotrophic activities in mammalian cells. 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