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Cell Competition Modifies Adult Stem Cell and Tissue Population Dynamics in a JAK-STAT-Dependent Manner.

Kolahgar G, Suijkerbuijk SJ, Kucinski I, Poirier EZ, Mansour S, Simons BD, Piddini E - Dev. Cell (2015)

Bottom Line: Throughout their lifetime, cells may suffer insults that reduce their fitness and disrupt their function, and it is unclear how these potentially harmful cells are managed in adult tissues.We address this question using the adult Drosophila posterior midgut as a model of homeostatic tissue and ribosomal Minute mutations to reduce fitness in groups of cells.Finally, we show that winner cell proliferation is fueled by the JAK-STAT ligand Unpaired-3, produced by Minute(-/+) cells in response to chronic JNK stress signaling.

View Article: PubMed Central - PubMed

Affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.

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JNK Activation Promotes the Clonal Expansion of Wild-Type Cells(A and B) puc-LacZ expression (α-β-Gal staining) in 3-day-old WT (FRT82B, pucA251/TM6B) (A) and M−/+ (B) guts (FRT82B, pucA251/FRT82B, RpS3∗).(C and D) Representative images of WT clones in M−/+ guts with (D and D′) or without (C and C′) continued expression of Puc in all progenitor cells and ECs from the time of clone induction (−RU486 and +RU486, C and D, respectively; hsflp/+; PSwitchALL/UAS Puc; FRT82B, ubiGFP, RpS3/FRT82B).(E) Analysis of clone-size distributions for WT clones either in WT guts (left) or in M−/+ guts (middle and right graphs), with (dark blue) or without (light blue) continued expression of Puc (as in C and D). Genotypes: left: hsflp/+; PSwitchALL/UAS Puc; FRT82B, ubiGFP/FRT82B; middle: hsflp/+; PSwitchALL/UAS Puc; FRT82B, ubiGFP, RpS3/FRT82B; right: hsflp/+; PSwitchPC/UAS Puc; FRT82B, ubiGFP, RpS3/FRT82B. p values (Mann-Whitney test) are indicated above each experiment.Scale bars represent 50 μm. See also Figure S3.
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fig5: JNK Activation Promotes the Clonal Expansion of Wild-Type Cells(A and B) puc-LacZ expression (α-β-Gal staining) in 3-day-old WT (FRT82B, pucA251/TM6B) (A) and M−/+ (B) guts (FRT82B, pucA251/FRT82B, RpS3∗).(C and D) Representative images of WT clones in M−/+ guts with (D and D′) or without (C and C′) continued expression of Puc in all progenitor cells and ECs from the time of clone induction (−RU486 and +RU486, C and D, respectively; hsflp/+; PSwitchALL/UAS Puc; FRT82B, ubiGFP, RpS3/FRT82B).(E) Analysis of clone-size distributions for WT clones either in WT guts (left) or in M−/+ guts (middle and right graphs), with (dark blue) or without (light blue) continued expression of Puc (as in C and D). Genotypes: left: hsflp/+; PSwitchALL/UAS Puc; FRT82B, ubiGFP/FRT82B; middle: hsflp/+; PSwitchALL/UAS Puc; FRT82B, ubiGFP, RpS3/FRT82B; right: hsflp/+; PSwitchPC/UAS Puc; FRT82B, ubiGFP, RpS3/FRT82B. p values (Mann-Whitney test) are indicated above each experiment.Scale bars represent 50 μm. See also Figure S3.

Mentions: Our data show that when cells of different fitness coexist in the adult fly gut, weak cells undergo frequent cell death whereas fit cells boost their tissue-colonization ability. Cell death is known to stimulate proliferation in nearby cells in several tissues, including the fly gut, through a phenomenon known as compensatory proliferation (Fan and Bergmann, 2008; Amcheslavsky et al., 2009). In addition, inhibiting cell death has been shown to block the overproliferation of fit cells during cell competition (de la Cova et al., 2004, 2014; Li and Baker, 2007). We therefore wondered whether protecting M−/+ cells from cell competition-induced apoptosis could mitigate the overgrowth of wild-type clones. Interestingly, we found that expressing the apoptosis inhibitor Diap1, which can effectively inhibit cell death in this tissue (Figures S3A–S3D), did not reduce the overgrowth of wild-type cells, whether it was expressed in ECs (Figure S3E) or expressed in both ECs and progenitor cells (Figures S3F and S3G). This suggested that signals other than apoptosis-induced proliferation might be involved. It has been reported that several mutants whose cells are outcompeted by wild-type cells, including M−/+, display chronic activation of the JNK signaling pathway in wing imaginal discs (Tamori and Deng, 2011). We therefore asked whether in the midgut, M−/+ cells also display increased JNK signaling. Indeed, we observed higher expression of puc-LacZ, a transcriptional reporter of JNK activation, in M−/+ midguts compared to control guts (Figures 5A and 5B), indicating that the pathway was activated.


Cell Competition Modifies Adult Stem Cell and Tissue Population Dynamics in a JAK-STAT-Dependent Manner.

Kolahgar G, Suijkerbuijk SJ, Kucinski I, Poirier EZ, Mansour S, Simons BD, Piddini E - Dev. Cell (2015)

JNK Activation Promotes the Clonal Expansion of Wild-Type Cells(A and B) puc-LacZ expression (α-β-Gal staining) in 3-day-old WT (FRT82B, pucA251/TM6B) (A) and M−/+ (B) guts (FRT82B, pucA251/FRT82B, RpS3∗).(C and D) Representative images of WT clones in M−/+ guts with (D and D′) or without (C and C′) continued expression of Puc in all progenitor cells and ECs from the time of clone induction (−RU486 and +RU486, C and D, respectively; hsflp/+; PSwitchALL/UAS Puc; FRT82B, ubiGFP, RpS3/FRT82B).(E) Analysis of clone-size distributions for WT clones either in WT guts (left) or in M−/+ guts (middle and right graphs), with (dark blue) or without (light blue) continued expression of Puc (as in C and D). Genotypes: left: hsflp/+; PSwitchALL/UAS Puc; FRT82B, ubiGFP/FRT82B; middle: hsflp/+; PSwitchALL/UAS Puc; FRT82B, ubiGFP, RpS3/FRT82B; right: hsflp/+; PSwitchPC/UAS Puc; FRT82B, ubiGFP, RpS3/FRT82B. p values (Mann-Whitney test) are indicated above each experiment.Scale bars represent 50 μm. See also Figure S3.
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Related In: Results  -  Collection

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fig5: JNK Activation Promotes the Clonal Expansion of Wild-Type Cells(A and B) puc-LacZ expression (α-β-Gal staining) in 3-day-old WT (FRT82B, pucA251/TM6B) (A) and M−/+ (B) guts (FRT82B, pucA251/FRT82B, RpS3∗).(C and D) Representative images of WT clones in M−/+ guts with (D and D′) or without (C and C′) continued expression of Puc in all progenitor cells and ECs from the time of clone induction (−RU486 and +RU486, C and D, respectively; hsflp/+; PSwitchALL/UAS Puc; FRT82B, ubiGFP, RpS3/FRT82B).(E) Analysis of clone-size distributions for WT clones either in WT guts (left) or in M−/+ guts (middle and right graphs), with (dark blue) or without (light blue) continued expression of Puc (as in C and D). Genotypes: left: hsflp/+; PSwitchALL/UAS Puc; FRT82B, ubiGFP/FRT82B; middle: hsflp/+; PSwitchALL/UAS Puc; FRT82B, ubiGFP, RpS3/FRT82B; right: hsflp/+; PSwitchPC/UAS Puc; FRT82B, ubiGFP, RpS3/FRT82B. p values (Mann-Whitney test) are indicated above each experiment.Scale bars represent 50 μm. See also Figure S3.
Mentions: Our data show that when cells of different fitness coexist in the adult fly gut, weak cells undergo frequent cell death whereas fit cells boost their tissue-colonization ability. Cell death is known to stimulate proliferation in nearby cells in several tissues, including the fly gut, through a phenomenon known as compensatory proliferation (Fan and Bergmann, 2008; Amcheslavsky et al., 2009). In addition, inhibiting cell death has been shown to block the overproliferation of fit cells during cell competition (de la Cova et al., 2004, 2014; Li and Baker, 2007). We therefore wondered whether protecting M−/+ cells from cell competition-induced apoptosis could mitigate the overgrowth of wild-type clones. Interestingly, we found that expressing the apoptosis inhibitor Diap1, which can effectively inhibit cell death in this tissue (Figures S3A–S3D), did not reduce the overgrowth of wild-type cells, whether it was expressed in ECs (Figure S3E) or expressed in both ECs and progenitor cells (Figures S3F and S3G). This suggested that signals other than apoptosis-induced proliferation might be involved. It has been reported that several mutants whose cells are outcompeted by wild-type cells, including M−/+, display chronic activation of the JNK signaling pathway in wing imaginal discs (Tamori and Deng, 2011). We therefore asked whether in the midgut, M−/+ cells also display increased JNK signaling. Indeed, we observed higher expression of puc-LacZ, a transcriptional reporter of JNK activation, in M−/+ midguts compared to control guts (Figures 5A and 5B), indicating that the pathway was activated.

Bottom Line: Throughout their lifetime, cells may suffer insults that reduce their fitness and disrupt their function, and it is unclear how these potentially harmful cells are managed in adult tissues.We address this question using the adult Drosophila posterior midgut as a model of homeostatic tissue and ribosomal Minute mutations to reduce fitness in groups of cells.Finally, we show that winner cell proliferation is fueled by the JAK-STAT ligand Unpaired-3, produced by Minute(-/+) cells in response to chronic JNK stress signaling.

View Article: PubMed Central - PubMed

Affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.

Show MeSH
Related in: MedlinePlus