Maintenance of the adult Drosophila intestine: all roads lead to homeostasis

Guo, Zheng; Lucchetta, Elena M.; Rafel, Neus; Ohlstein, Benjamin

doi:10.1016/j.gde.2016.06.009

Cited by 82 publications

(85 citation statements)

References 62 publications

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“…To investigate what damage-induced signals activate the RSCs, we examined damage pathways known to activate ISC proliferation. Extensive studies have shown that the EGFR/MAPK, Jak/Stat, Wnt, Hippo, PVF, JNK, Insulin, and BMP pathways are all involved in eliciting ISC division either under steady state conditions or during regeneration following cellular damage (Gervais and Bardin, 2017;Guo et al, 2016;Jiang et al, 2016;Li and Jasper, 2016). Reporters for four of these pathways, JNK, Jak/Stat, MAPK and Yki pathways were induced upon surgical injury ( Figure S3).…”

Section: Damage Activates Quiescent Rscs Via Upregulation Of Multiplementioning

confidence: 99%

An abundant quiescent stem cell population inDrosophilaMalpighian tubules protects principal cells from kidney stones

Wang

Spradling

2019

Preprint

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Adult Drosophila Malpighian tubules have low rates of cell turnover but are vulnerable to damage caused by stones, like their mammalian counterparts, kidneys. We show that Drosophila renal stem cells (RSCs) comprise a unique, unipotent regenerative compartment. RSCs respond only to loss of nearby principal cells (PCs), cells critical for maintaining ionic balance. Perhaps due to the large size of PCs they are outnumbered by RSCs, which replace each lost cell with multiple PCs of lower ploidy. RSCs share a developmental origin with highly active intestinal stem cells (ISCs), and like ISCs generate daughters by asymmetric Notch signaling, yet RSCs remain quiescent in the absence of damage. Nevertheless, the capacity for RSC-mediated repair extends the lifespan of flies carrying kidney stones. We propose that abundant, RSC-like stem cells exist in other tissues with low rates of turnover where they may have been mistaken for differentiated tissue cells.

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Section: Damage Activates Quiescent Rscs Via Upregulation Of Multiplementioning

confidence: 99%

An abundant quiescent stem cell population inDrosophilaMalpighian tubules protects principal cells from kidney stones

Wang

Spradling

2019

Preprint

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“…A Ret/wingless positive feedback loop promotes stem cell proliferation in the adult Drosophila intestine Several mitogenic signals have been shown to promote stem cell proliferation when mis-or over-expressed from adult intestinal progenitors (Jiang & Edgar, 2012;Guo et al, 2016;Jiang et al, 2016). To begin to explore the signalling context in which Ret may function, we tested the ability of such mitogens to stimulate proliferation of adult intestinal progenitors with reduced Ret expression.…”

Section: Ret Sustains Stem Cell Proliferation In the Adult Drosophilamentioning

confidence: 99%

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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“…The Drosophila adult gut is made up of three cell types: differentiated enterocytes (ECs), entero-endocrine cells (EEs), and intestinal stem cells (ISCs) (Figure 1A-B, (34)). Expression of a phosphorylation-defective and therefore constitutively active form of Yki in the ISCs ( esg-Gal4 Gal80 ts > UAS-yki 3SA , referred to as esg ts >yki 3SA ) triggers ISC over-proliferation (32) (Figure 1C, Figure S1A), as revealed by increased 5-ethynyl-2 deoxyuridine (EdU) uptake (Figure S1B), Phospho-Histone H3 (PH3) staining (Figure S1C), and elevated expression of matrix metalloproteinase genes (MMPs) (Figure S1D).…”

Section: Resultsmentioning

confidence: 99%

ADrosophilamodel of oral peptide therapeutics for adult Intestinal Stem Cell tumors

Bajpai

Ahmad

Tang

et al. 2020

Preprint

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The proto-oncogene YAP /Yki, a transcription co-factor of the Hippo pathway, has been linked to many cancers. YAP interacts with DNA-binding TEAD/Sd proteins to regulate expression of its transcriptional targets. Disruption of YAP-TEAD therefore offers a potential therapeutic strategy. The mammalian Vestigial Like (VGLL) protein, specifically its TONDU domain, has been shown to competitively inhibit YAP-TEAD interaction and a TONDU peptide can suppress YAP-induced cancer. As TONDU could potentially be developed into a therapeutic peptide for multiple cancers, we evaluated its efficacy in Yki-driven adult Intestinal Stem Cell (ISC) tumors in Drosophila. We show that oral uptake of the TONDU peptide is highly effective at inhibiting Yki-driven gut tumors by suppressing YAP-TEAD interaction. Comparative proteomics of early and late stage Yki-driven ISC tumors revealed enrichment of a number of proteins, including members of the integrin signaling pathway, such as Talin, Vinculin and Paxillin. These, in turn displayed a decrease in their levels in TONDU-peptide treated tumors. Further, we show that Sd binds to the regulatory region of integrin-coding gene, mew, which codes for αPS1, a key integrin of the ISCs. In support to a possible role of integrins in Yki-driven ISC tumors, we show that genetic downregulation of mew arrests Yki-driven ISC proliferation, reminiscent of the effects of TONDU peptide. Altogether, our findings present a novel platform for screening therapeutic peptides and provide insights into tumor suppression mechanisms.SIGNIFICANCE STATEMENTDiscovering novel strategies to inhibit oncogene activity is a priority in cancer biology. As signaling pathways are widely conserved between mammals and Drosophila, these questions can be effectively addressed in this model organism. Here, we show that progression of Drosophila Intestinal Stem Cell (ISC) tumors induced by gain of an oncogenic form of the transcription co-factor Yki can be suppressed by feeding a peptide corresponding to the conserved TONDU domain of Vestigial (Vg), which blocks binding of Yki to the Sd transcription factor. Further, we show that down regulation of the integrin signaling pathway is causally linked to TONDU-peptide-mediated ISC tumor suppression. Our findings reveal that Drosophila can be successfully used to screen peptides for their therapeutic applications.

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Maintenance of the adult Drosophila intestine: all roads lead to homeostasis

Cited by 82 publications

References 62 publications

An abundant quiescent stem cell population inDrosophilaMalpighian tubules protects principal cells from kidney stones

An abundant quiescent stem cell population inDrosophilaMalpighian tubules protects principal cells from kidney stones

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

ADrosophilamodel of oral peptide therapeutics for adult Intestinal Stem Cell tumors

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