Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

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

SN - 0261-4189

VL - 36

SP - 3029

EP - 3045

JO - E M B O Journal

JF - E M B O Journal

IS - 20

ER -