Src kinase function controls progenitor cell pools during regeneration and tumor onset in the Drosophila intestine

Kohlmaier, Alexander; Jin, Yinhua; Reuter, Hanna; Begum, Julfa; Dutta, Devanjali; Edgar, Bruce A.

doi:10.1038/onc.2014.163

Cited by 42 publications

(62 citation statements)

References 99 publications

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“…Experiments in which we simultaneously over‐expressed Ret and downregulated Src42A or Src64B (the two Src kinases in Drosophila ) from adult intestinal progenitors confirmed that Src42A , but not Src64B , is required for both Ret ‐driven hyperplasia and activation of Wg ligand in intestinal progenitors (Fig 4C). The existence of positive feedback between Ret and Wg pathways via Src42A was further suggested by the fact that activation of Src42A upregulated Wg ligand in intestinal progenitors (Fig 4D), and by our finding that the previously reported proliferation increase resulting from Src42A activation (Cordero et al , 2014; Kohlmaier et al , 2015) was, at least partially, Ret ‐dependent (Fig 4E).…”

Section: Resultssupporting

confidence: 69%

“…Consistent with this biochemical interaction, we observed that, in addition to upregulating Wg, Ret over‐expression in adult intestinal progenitors also resulted in enhanced phospho‐Src immunoreactivity (Fig 4B), suggestive of Src kinase activation. Activation of Src cytoplasmic tyrosine kinases is frequently implicated in signal transduction downstream of transmembrane receptors, and modulation of Src levels in intestinal progenitors results in phenotypes similar to those described above for Ret depletion/over‐expression (Cordero et al , 2014; Kohlmaier et al , 2015), suggesting that Ret‐induced hyperproliferation may require Src kinases. Experiments in which we simultaneously over‐expressed Ret and downregulated Src42A or Src64B (the two Src kinases in Drosophila ) from adult intestinal progenitors confirmed that Src42A , but not Src64B , is required for both Ret ‐driven hyperplasia and activation of Wg ligand in intestinal progenitors (Fig 4C).…”

Section: Resultsmentioning

confidence: 66%

“…The finding that, in the Drosophila intestine, Src kinases control expression of a mitogenic module consisting of String/Cdc25 and cyclin E (Kohlmaier et al , 2015) provides a simple link between Ret activation and its pro‐proliferative effects. Overactive Src kinases do, however, lead to intestinal tumours (Kohlmaier et al , 2015) so mechanisms must be in place to limit the positive Ret/Wg feedback loop so that it sustains homeostatic proliferation, but does not result in tumour formation. Availability of Wg ligand may be an extrinsic mechanism, but the focal adhesion kinase Fak may provide a cell‐intrinsic break downstream of Ret/Src activation.…”

Section: Discussionmentioning

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: Resultssupporting

confidence: 69%

Section: Resultsmentioning

confidence: 66%

Section: Discussionmentioning

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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“…For example, Drosophila simple columnar epithelia such as imaginal discs rely primarily on apical Crb-Mer/Ex-Kibra-Sav signalling to retain Yki in the cytoplasm and restrict tissue growth (Baumgartner et al, 2010;Chen et al, 2010;Genevet et al, 2010;Hamaratoglu et al, 2006;Ling et al, 2010;Yu et al, 2010). By contrast, Drosophila stratified columnar epithelia such as the intestine require integrins, Src, EGFR and Yki to promote proliferation of basal layer stem/progenitor cells, suggesting that the regulatory connection between them described here is also conserved (Cordero et al, 2014;Jiang et al, 2011;Kohlmaier et al, 2015;Lin et al, 2013;Shaw et al, 2010;Staley and Irvine, 2010;Xu et al, 2011). Furthermore, ectopic activation of Src, EGFR, PI3K or Yki in simple columnar imaginal discs is sufficient to induce overproliferation of cells, whereas loss of PI3K or Yki strongly impairs imaginal disc tumour formation (Doggett et al, 2011;Enomoto and Igaki, 2013;Fernandez et al, 2014;Herranz et al, 2012Herranz et al, , 2014Strassburger et al, 2012;Willecke et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Integrin signalling regulates YAP and TAZ to control skin homeostasis

Elbediwy¹,

Vincent‐Mistiaen²,

Spencer‐Dene³

et al. 2016

Journal of Cell Science

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The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib.

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“…To confirm these TS-MARCM results, we used a second method for distinguishing symmetric from asymmetric ISC divisions in homozygous control or lin-28 Δ1 mutant intestines (Kohlmaier et al, 2015). In this approach, a GFP-tagged version of the localization domain of Partner of Numb (Pon::GFP) was expressed specifically in ISCs.…”

Section: Lin-28 Promotes Isc Symmetric Renewalmentioning

confidence: 99%

Lin-28 promotes symmetric stem cell division and drives adaptive growth in the adult Drosophila intestine

2015

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Stem cells switch between asymmetric and symmetric division to expand in number as tissues grow during development and in response to environmental changes. The stem cell intrinsic proteins controlling this switch are largely unknown, but one candidate is the Lin-28 pluripotency factor. A conserved RNA-binding protein that is downregulated in most animals as they develop from embryos to adults, Lin-28 persists in populations of adult stem cells. Its function in these cells has not been previously characterized. Here, we report that Lin-28 is highly enriched in adult intestinal stem cells in the Drosophila intestine. lin-28 null mutants are homozygous viable but display defects in this population of cells, which fail to undergo a characteristic food-triggered expansion in number and have reduced rates of symmetric division as well as reduced insulin signaling. Immunoprecipitation of Lin-28-bound mRNAs identified Insulin-like Receptor (InR), forced expression of which completely rescues lin-28-associated defects in intestinal stem cell number and division pattern. Furthermore, this stem cell activity of lin-28 is independent of one well-known lin-28 target, the microRNA let-7, which has limited expression in the intestinal epithelium. These results identify Lin-28 as a stem cell intrinsic factor that boosts insulin signaling in intestinal progenitor cells and promotes their symmetric division in response to nutrients, defining a mechanism through which Lin-28 controls the adult stem cell division patterns that underlie tissue homeostasis and regeneration.

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Src kinase function controls progenitor cell pools during regeneration and tumor onset in the Drosophila intestine

Cited by 42 publications

References 99 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

Integrin signalling regulates YAP and TAZ to control skin homeostasis

Lin-28 promotes symmetric stem cell division and drives adaptive growth in the adult Drosophila intestine

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