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Loss of Drosophila pseudouridine synthase triggers apoptosis-induced proliferation and promotes cell-nonautonomous EMT.

Vicidomini R, Di Giovanni A, Petrizzo A, Iannucci LF, Benvenuto G, Nagel AC, Preiss A, Furia M - Cell Death Dis (2015)

Bottom Line: Here we show that localized depletion of this enzyme can act as an endogenous stimulus capable of triggering apoptosis-induced proliferation, and that context-dependent effects are elicited in different sub-populations of the silenced cells.Unexpectedly, cell-nonautonomous effects, such as epithelial mesenchymal transition in the contiguous unsilenced squamous epithelium, are also promoted.On this account, our results can add new light on the still unexplained tumor predisposition that characterizes X-linked dyskeratosis, the human disease caused by reduced pseudouridine synthase activity.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Biologia, Università di Napoli 'Federico II', via Cinthia, Naples 80126, Italy.

ABSTRACT
Many developing tissues display regenerative capability that allows them to compensate cell loss and preserve tissue homeostasis. Because of their remarkable regenerative capability, Drosophila wing discs are extensively used for the study of regenerative phenomena. We thus used the developing wing to investigate the role played in tissue homeostasis by the evolutionarily conserved eukaryotic H/ACA small nucleolar ribonucleoprotein pseudouridine synthase. Here we show that localized depletion of this enzyme can act as an endogenous stimulus capable of triggering apoptosis-induced proliferation, and that context-dependent effects are elicited in different sub-populations of the silenced cells. In fact, some cells undergo apoptosis, whereas those surrounding the apoptotic foci, although identically depleted, overproliferate. This overproliferation correlates with ectopic induction of the Wg and JAK-STAT (Janus kinase-signal transducer and activator of transcription) mitogenic pathways. Expression of a p35 transgene, which blocks the complete execution of the death program and generates the so-called 'undead cells', amplifies the proliferative response. Pseudouridine synthase depletion also causes loss of apicobasal polarity, disruption of adherens cell junctions and ectopic induction of JNK (c-Jun N-terminal kinase) and Mmp1 (matrix metalloproteinase-1) activity, leading to a significant epithelial reorganization. Unexpectedly, cell-nonautonomous effects, such as epithelial mesenchymal transition in the contiguous unsilenced squamous epithelium, are also promoted. Collectively, these data point out that cell-cell communication and long-range signaling can take a relevant role in the response to pseudouridine synthase decline. Considering that all the affected pathways are highly conserved throughout evolution, it is plausible that the response to pseudouridine synthase depletion has been widely preserved. On this account, our results can add new light on the still unexplained tumor predisposition that characterizes X-linked dyskeratosis, the human disease caused by reduced pseudouridine synthase activity.

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Mfl depletion triggers ectopic activation of JAK-STAT signaling. Confocal analysis of wing discs collected at 120 h AED carrying the 10XSTAT-dGFP reporter (the use of destabilized dGFP69 allows to visualize real-time activation of the reporter). (a) No activity of the reporter was detectable in the wing pouch of control discs, whereas JAK-STAT expression is detected in the presumptive wing hinge (blue arrow). (b) In omb>IRmfl silenced discs (v46282 line in the picture), the reporter was overexpressed in the wing hinge (blue arrow) and ectopically induced in the dorsal area of the omb domain (white arrows), where it, in part, surrounded and overlapped the domain of Wg induction. In the ventral region (yellow arrows), JAK-STAT ectopic induction encircled Wg accumulation. DAPI (4',6-diamidino-2-phenylindole) is in blue, Wg in red and GFP in green
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fig5: Mfl depletion triggers ectopic activation of JAK-STAT signaling. Confocal analysis of wing discs collected at 120 h AED carrying the 10XSTAT-dGFP reporter (the use of destabilized dGFP69 allows to visualize real-time activation of the reporter). (a) No activity of the reporter was detectable in the wing pouch of control discs, whereas JAK-STAT expression is detected in the presumptive wing hinge (blue arrow). (b) In omb>IRmfl silenced discs (v46282 line in the picture), the reporter was overexpressed in the wing hinge (blue arrow) and ectopically induced in the dorsal area of the omb domain (white arrows), where it, in part, surrounded and overlapped the domain of Wg induction. In the ventral region (yellow arrows), JAK-STAT ectopic induction encircled Wg accumulation. DAPI (4',6-diamidino-2-phenylindole) is in blue, Wg in red and GFP in green

Mentions: Proliferation of the silenced cells also correlated with upregulation and ectopic induction of JAK-STAT, another proliferative pathway associated with apoptosis-induced proliferation and regeneration.30, 31 As shown in Figure 5, this pathway is upregulated at the center of the inner ring, and ectopically activated at specific regions of the silenced domain. In the V compartment, its induction surrounded the areas showing Wg accumulation, whereas in the dorsal part it encircled and in part overlapped Wg ectopic expression. Altogether, these data indicate that Mfl depletion induces a regenerative response, which, as observed in other cases,32 in the presence of p35 results in a pronounced hyperplastic phenotype.


Loss of Drosophila pseudouridine synthase triggers apoptosis-induced proliferation and promotes cell-nonautonomous EMT.

Vicidomini R, Di Giovanni A, Petrizzo A, Iannucci LF, Benvenuto G, Nagel AC, Preiss A, Furia M - Cell Death Dis (2015)

Mfl depletion triggers ectopic activation of JAK-STAT signaling. Confocal analysis of wing discs collected at 120 h AED carrying the 10XSTAT-dGFP reporter (the use of destabilized dGFP69 allows to visualize real-time activation of the reporter). (a) No activity of the reporter was detectable in the wing pouch of control discs, whereas JAK-STAT expression is detected in the presumptive wing hinge (blue arrow). (b) In omb>IRmfl silenced discs (v46282 line in the picture), the reporter was overexpressed in the wing hinge (blue arrow) and ectopically induced in the dorsal area of the omb domain (white arrows), where it, in part, surrounded and overlapped the domain of Wg induction. In the ventral region (yellow arrows), JAK-STAT ectopic induction encircled Wg accumulation. DAPI (4',6-diamidino-2-phenylindole) is in blue, Wg in red and GFP in green
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385944&req=5

fig5: Mfl depletion triggers ectopic activation of JAK-STAT signaling. Confocal analysis of wing discs collected at 120 h AED carrying the 10XSTAT-dGFP reporter (the use of destabilized dGFP69 allows to visualize real-time activation of the reporter). (a) No activity of the reporter was detectable in the wing pouch of control discs, whereas JAK-STAT expression is detected in the presumptive wing hinge (blue arrow). (b) In omb>IRmfl silenced discs (v46282 line in the picture), the reporter was overexpressed in the wing hinge (blue arrow) and ectopically induced in the dorsal area of the omb domain (white arrows), where it, in part, surrounded and overlapped the domain of Wg induction. In the ventral region (yellow arrows), JAK-STAT ectopic induction encircled Wg accumulation. DAPI (4',6-diamidino-2-phenylindole) is in blue, Wg in red and GFP in green
Mentions: Proliferation of the silenced cells also correlated with upregulation and ectopic induction of JAK-STAT, another proliferative pathway associated with apoptosis-induced proliferation and regeneration.30, 31 As shown in Figure 5, this pathway is upregulated at the center of the inner ring, and ectopically activated at specific regions of the silenced domain. In the V compartment, its induction surrounded the areas showing Wg accumulation, whereas in the dorsal part it encircled and in part overlapped Wg ectopic expression. Altogether, these data indicate that Mfl depletion induces a regenerative response, which, as observed in other cases,32 in the presence of p35 results in a pronounced hyperplastic phenotype.

Bottom Line: Here we show that localized depletion of this enzyme can act as an endogenous stimulus capable of triggering apoptosis-induced proliferation, and that context-dependent effects are elicited in different sub-populations of the silenced cells.Unexpectedly, cell-nonautonomous effects, such as epithelial mesenchymal transition in the contiguous unsilenced squamous epithelium, are also promoted.On this account, our results can add new light on the still unexplained tumor predisposition that characterizes X-linked dyskeratosis, the human disease caused by reduced pseudouridine synthase activity.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Biologia, Università di Napoli 'Federico II', via Cinthia, Naples 80126, Italy.

ABSTRACT
Many developing tissues display regenerative capability that allows them to compensate cell loss and preserve tissue homeostasis. Because of their remarkable regenerative capability, Drosophila wing discs are extensively used for the study of regenerative phenomena. We thus used the developing wing to investigate the role played in tissue homeostasis by the evolutionarily conserved eukaryotic H/ACA small nucleolar ribonucleoprotein pseudouridine synthase. Here we show that localized depletion of this enzyme can act as an endogenous stimulus capable of triggering apoptosis-induced proliferation, and that context-dependent effects are elicited in different sub-populations of the silenced cells. In fact, some cells undergo apoptosis, whereas those surrounding the apoptotic foci, although identically depleted, overproliferate. This overproliferation correlates with ectopic induction of the Wg and JAK-STAT (Janus kinase-signal transducer and activator of transcription) mitogenic pathways. Expression of a p35 transgene, which blocks the complete execution of the death program and generates the so-called 'undead cells', amplifies the proliferative response. Pseudouridine synthase depletion also causes loss of apicobasal polarity, disruption of adherens cell junctions and ectopic induction of JNK (c-Jun N-terminal kinase) and Mmp1 (matrix metalloproteinase-1) activity, leading to a significant epithelial reorganization. Unexpectedly, cell-nonautonomous effects, such as epithelial mesenchymal transition in the contiguous unsilenced squamous epithelium, are also promoted. Collectively, these data point out that cell-cell communication and long-range signaling can take a relevant role in the response to pseudouridine synthase decline. Considering that all the affected pathways are highly conserved throughout evolution, it is plausible that the response to pseudouridine synthase depletion has been widely preserved. On this account, our results can add new light on the still unexplained tumor predisposition that characterizes X-linked dyskeratosis, the human disease caused by reduced pseudouridine synthase activity.

Show MeSH
Related in: MedlinePlus