Patterning and growth control by membrane-tethered Wingless

Alexandre, Cyrille; Baena-Lopez, Alberto; Vincent, Jean‐Paul

doi:10.1038/nature12879

Cited by 280 publications

(348 citation statements)

References 39 publications

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“…Despite abundant genetic evidence that Wg signalling promotes stem cell proliferation in flies (Lin et al , 2008; Cordero et al , 2012; Tian et al , 2016), the source of Wg has remained unclear. Using new, improved tools to visualise Wg expression (Alexandre et al , 2014), our findings lend further support to recent data (Tian et al , 2016) indicating that the source of Wg ligand is not the stem cells themselves, despite the striking Ret‐driven upregulation of Wg on their surface. How might Ret signalling in adult intestinal progenitors lead to Wg protein upregulation in these cells without affecting its transcript?…”

Section: Discussionsupporting

confidence: 87%

“…This suggested that the increased Wg protein observed following Ret expression may result from a non‐transcriptional mechanism. To confirm this, we analysed wg transcription with cell specificity by making use of wg KO ‐Gal4 : a wg transcription reporter in which Gal4 is expressed under the control of the endogenous wg promoter (Alexandre et al , 2014). As described in a previous study (Tian et al , 2016), we found no expression of this reporter in adult intestinal stem cells (Fig 3E), but were able to detect it at intestinal compartment boundaries (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Su(H)‐LacZ [ Su(H) GBE ‐LacZ , (Furriols & Bray, 2001)], esg‐Gal4 NP7397 , UAS‐GFP , tub‐Gal80 TS chromosome (gift from J. de Navascués), Ret‐Gal4 (Walker et al , 2013), wg KO ‐Gal4 (Alexandre et al , 2014; gift from Luis‐Alberto Baena‐Lopez).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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“…Endocytosis also mediates Arrow-directed degradation necessary for the observed Wg distribution and signaling (14). However, rescue of patterning is observed even upon replacement of the endogenous Wg with a transmembrane-tethered Wg, thus raising questions on the importance of a secreted Wg gradient (15). Regardless, inhibition of endocytosis in the recipient cells, by using the dominant-negative (DN) or the temperature-sensitive form of shibire, demonstrates the importance of dynamin-dependent endocytosis in Wg-mediated signaling (11,13).…”

mentioning

confidence: 99%

Endocytosis of Wingless via a dynamin-independent pathway is necessary for signaling in Drosophila wing discs

Hemalatha

Prabhakara

Mayor

2016

Proc. Natl. Acad. Sci. U.S.A.

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Endocytosis of ligand-receptor complexes regulates signal transduction during development. In particular, clathrin and dynamin-dependent endocytosis has been well studied in the context of patterning of the Drosophila wing disc, wherein apically secreted Wingless (Wg) encounters its receptor, DFrizzled2 (DFz2), resulting in a distinctive dorso-ventral pattern of signaling outputs. Here, we directly track the endocytosis of Wg and DFz2 in the wing disc and demonstrate that Wg is endocytosed from the apical surface devoid of DFz2 via a dynamin-independent CLIC/GEEC pathway, regulated by Arf1, Garz, and class I PI3K. Subsequently, Wg containing CLIC/GEEC endosomes fuse with DFz2-containing vesicles derived from the clathrin and dynamin-dependent endocytic pathway, which results in a low pH-dependent transfer of Wg to DFz2 within the merged and acidified endosome to initiate Wg signaling. The employment of two distinct endocytic pathways exemplifies a mechanism wherein cells in tissues leverage multiple endocytic pathways to spatially regulate signaling.clathrin and dynamin-independent endocytosis | Wingless signaling | pH of endosome | wing disc development | Garz localization

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“…We also looked at flies expressing a membrane-tethered form of Wg (NRT-Wg) from the endogenous wg locus (Alexandre et al, 2015). Anti-Wg again showed high Wg signals at the pylorus, with no obvious signalling gradient ( Figure 1E,E').…”

mentioning

confidence: 99%

Autocrine and paracrine Wingless signalling in the Drosophila midgut by both continuous gradient and asynchronous bursts of wingless expression

2016

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Wingless (Wg)/ Wnt signalling is a major regulator of homeostasis in both the mammalian and Drosophila intestine. In Drosophila the organisation and function of Wingless signalling in the adult intestine remain poorly understood. Here we characterise the pattern of expression of wg, the stabilisation of its effector Armadillo in the adult Drosophila midgut, and correlate them with the response of the cells to Wg signalling activation. We show that in normal homeostasis there is a gradient of Wingless signalling in the intestinal stem cell (ISC) and the undifferentiated progenitor cell (enteroblast, EB) populations along the posterior midgut, with a high point at the midgut-hindgut boundary (pylorus). This gradient results from a combination of two sources of Wingless: a distant source outside the epithelium (the pylorus) and a local one from the ISCs and EBs themselves. Altogether, our studies show that Wingless expression and signalling in the epithelium is not continuous, but operates through bursts that occur randomly in space and time.

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Patterning and growth control by membrane-tethered Wingless

Cited by 280 publications

References 39 publications

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

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

Endocytosis of Wingless via a dynamin-independent pathway is necessary for signaling in Drosophila wing discs

Autocrine and paracrine Wingless signalling in the Drosophila midgut by both continuous gradient and asynchronous bursts of wingless expression

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