Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia
Research output: Contribution to journal › Journal article › peer-review
Standard
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 Journal, Vol. 36, No. 20, 16.10.2017, p. 3029-3045.Research output: Contribution to journal › Journal article › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
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
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 - Drosophila
KW - enteroendocrine
KW - intestine
KW - Ret
KW - stem cell
U2 - 10.15252/embj.201696247
DO - 10.15252/embj.201696247
M3 - Journal article
C2 - 28899900
AN - SCOPUS:85031501229
VL - 36
SP - 3029
EP - 3045
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
IS - 20
ER -
ID: 185237059