Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia
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Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia. / Perea, Daniel; Guiu, Jordi; Hudry, Bruno; Konstantinidou, Chrysoula; Milona, Alexandra; Hadjieconomou, Dafni; Carroll, Thomas; Hoyer, Nina; Natarajan, Dipa; Kallijärvi, Jukka; Walker, James A; Soba, Peter; Thapar, Nikhil; Burns, Alan J; Jensen, Kim B; Miguel-Aliaga, Irene.
in: EMBO J, Jahrgang 36, Nr. 20, 16.10.2017, S. 3029-3045.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia
AU - Perea, Daniel
AU - Guiu, Jordi
AU - Hudry, Bruno
AU - Konstantinidou, Chrysoula
AU - Milona, Alexandra
AU - Hadjieconomou, Dafni
AU - Carroll, Thomas
AU - Hoyer, Nina
AU - Natarajan, Dipa
AU - Kallijärvi, Jukka
AU - Walker, James A
AU - Soba, Peter
AU - Thapar, Nikhil
AU - Burns, Alan J
AU - Jensen, Kim B
AU - Miguel-Aliaga, Irene
N1 - © 2017 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2017/10/16
Y1 - 2017/10/16
N2 - 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.
AB - 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.
KW - Animals
KW - Cell Differentiation
KW - Cell Proliferation
KW - Drosophila
KW - Epithelial Cells
KW - Gene Expression Regulation
KW - Humans
KW - Intestinal Mucosa
KW - Mice
KW - Proto-Oncogene Proteins c-ret
KW - Wnt Signaling Pathway
KW - Journal Article
U2 - 10.15252/embj.201696247
DO - 10.15252/embj.201696247
M3 - SCORING: Journal article
C2 - 28899900
VL - 36
SP - 3029
EP - 3045
JO - EMBO J
JF - EMBO J
SN - 0261-4189
IS - 20
ER -