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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: 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.We also find that competition induces stem cell proliferation and self-renewal in healthy tissue, promoting selective advantage and tissue colonization.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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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: 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.We also find that competition induces stem cell proliferation and self-renewal in healthy tissue, promoting selective advantage and tissue colonization.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