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

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.

TheDrosophila Retgene functions in the stomatogastric nervous system with the Maverick TGFβ ligand and theGfrlco-receptor

“…Similarly, for the rescue experiments, lack of statistically significant rescue in the frontal or esophageal ganglia might be due to the variability of these structures or the promoter used might lack adequate expression. In adult flies, Ret function is required in epithelial cells of the intestine (Perea et al, 2017). The Ret-GAL4 lines used express in the epithelial lining of the embryonic midgut, particularly in the earlier stages (Hernández et al, 2015), so we cannot rule out Ret function in the gut as a cause for the SNS patterning defects.…”

“…Homologs of the RET and GFR receptors are present in invertebrates but are thought to function independently of each other, with GFRs operating in conjunction with Fas2/NCAM rather than with a soluble ligand (Kallijärvi et al, 2012) and RET operating with integrins (Soba et al, 2015). In Drosophila, the RET gene (Ret) is expressed by enteric neurons and epithelial progenitor cells of the adult midgut and is required for homeostasis of these populations (Perea et al, 2017). In the Drosophila embryo, Ret is expressed in the developing stomatogastric nervous system (SNS), a population of cells that delaminate and migrate along the developing gut to form the enteric nervous system (ENS), and Ret is also expressed in the Malpighian tubules, the fly equivalent of the kidney (Hahn and Bishop, 2001;Copenhaver, 2007;Hartenstein, 1997).…”

Ret and Substrate-Derived TGF-β Maverick Regulate Space-Filling Dendrite Growth in Drosophila Sensory Neurons

“…Thus, it seems plausible that Mav and Ret form a functional signaling pair here too, although neither GFRL nor classical TGF-β receptors play a role in space-filling dendrite growth of C4da neurons. Moreover, although Drosophila Ret has tyrosine kinase activity, which is required in other contexts (Abrescia et al, 2005; Perea et al, 2017), our findings suggest that it might play a lesser role in C4da neuron dendrite patterning. Thus, Ret function in this system likely requires additional co-receptors.…”

Drosophila flies high over the Asia–Pacific: Report on the Fourth Asia–Pacific Drosophila Research Conference

“…For example, Dr. Erina Kuranaga (Tohoku University, Japan) gave a talk entitled "Collective cell movement during epithelial morphogenesis." She also presented work describing roles for the Ret receptor tyrosine kinase, better known for its roles in the enteric nervous system, in the intestinal epithelium of both flies and mice (Perea et al, 2017). Using a computer simulation, they showed that the collective cell movement was driven by left-right asymmetric cell intercalation, which was also observed in vivo (Sato et al, 2015).…”

“…Notably, they also discovered that sexual identity is reversible and can be reprogrammed in nongonadal organs such as the gut (Hudry, Khadayate, & Miguel-Aliaga, 2016). She also presented work describing roles for the Ret receptor tyrosine kinase, better known for its roles in the enteric nervous system, in the intestinal epithelium of both flies and mice (Perea et al, 2017).…”