Limits...
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.

Show MeSH
Wild-Type Cells Induce Clonal Extinction and Stem Cell Loss in M−/+ Tissues(A–D) Independently labeled M−/+ and WT clones were induced in M−/+ guts and their fate was analyzed at 4 (A–A″′, C, and D), 9 (C and D), and 15 (B–B″′, C, and D) days ACI. WT clones are GFP−, whereas M−/+ cells are GFP+. A simultaneous but independent recombination event marks clones by 0×RFP (red fluorescent protein) in an otherwise 1×RFP or 2×RFP tissue, allowing lineage tracing in M−/+ (and in WT) tissue (hsflp; FRT40, ubiRFP/FRT40; FRT82B, ubiGFP, RpS3/FRT82B).(C) Diagram showing the evolution of clone number (expressed as a fraction of the average clone number at 4 days) for WT clones competing in M−/+ tissue (n = 78, 78, and 101 clones at 4, 9, and 15 days ACI, respectively), competing M−/+ clones (0×RFP) from the same guts (genotype as in A) (n = 96, 73, and 45 clones at 4, 9, and 15 days ACI, respectively), and neutral M−/+ clones (0×RFP) in wholly M−/+ guts (hsflp; FRT40, ubiRFP/FRT40; FRT82B, ubiGFP, RpS3/TM2) (n = 142, 41, and 65 clones at 4, 9, and 15 days ACI, respectively).(D) Evolution of median clone size (genotypes and datasets are as in C).(C and D) ∗p < 0.05, ∗∗p < 0.02, Mann-Whitney test. Error bars represent SEM.(E–F′) Six-day-old GFP+M−/+ clones (green) in control M−/+ guts (E and E′) (Df(1)R194, w/hsflp, actGal4, UAS CD8GFP; FRT40, tubGal80/FRT40) or in pseudo-WT guts (F and F′) (Df(1)R194, w/hsflp, actGal4, UAS CD8GFP; FRT40, tubGal80, P[RpL36+w+]/FRT40) stained for Dl (red). The arrows indicate a multicellular clone devoid of Dl+ cells.(G) Size distribution of clones as in (E) (blue bars; n = 14 clones of two cells or more) and (F) (red bars; n = 17 clones of two cells or more).(H) Bar graphs showing the distribution of clones based on their Dl+ cell content for M−/+ clones in M−/+ guts (n = 30 clones) and for M−/+ clones in WT guts (n = 47 clones). Note the reduction in Dl+ clones for M−/+ clones in a WT background and the appearance of a large fraction of multicellular clones devoid of Dl+ cells.Scale bars represent 50 μm.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4537514&req=5

fig2: Wild-Type Cells Induce Clonal Extinction and Stem Cell Loss in M−/+ Tissues(A–D) Independently labeled M−/+ and WT clones were induced in M−/+ guts and their fate was analyzed at 4 (A–A″′, C, and D), 9 (C and D), and 15 (B–B″′, C, and D) days ACI. WT clones are GFP−, whereas M−/+ cells are GFP+. A simultaneous but independent recombination event marks clones by 0×RFP (red fluorescent protein) in an otherwise 1×RFP or 2×RFP tissue, allowing lineage tracing in M−/+ (and in WT) tissue (hsflp; FRT40, ubiRFP/FRT40; FRT82B, ubiGFP, RpS3/FRT82B).(C) Diagram showing the evolution of clone number (expressed as a fraction of the average clone number at 4 days) for WT clones competing in M−/+ tissue (n = 78, 78, and 101 clones at 4, 9, and 15 days ACI, respectively), competing M−/+ clones (0×RFP) from the same guts (genotype as in A) (n = 96, 73, and 45 clones at 4, 9, and 15 days ACI, respectively), and neutral M−/+ clones (0×RFP) in wholly M−/+ guts (hsflp; FRT40, ubiRFP/FRT40; FRT82B, ubiGFP, RpS3/TM2) (n = 142, 41, and 65 clones at 4, 9, and 15 days ACI, respectively).(D) Evolution of median clone size (genotypes and datasets are as in C).(C and D) ∗p < 0.05, ∗∗p < 0.02, Mann-Whitney test. Error bars represent SEM.(E–F′) Six-day-old GFP+M−/+ clones (green) in control M−/+ guts (E and E′) (Df(1)R194, w/hsflp, actGal4, UAS CD8GFP; FRT40, tubGal80/FRT40) or in pseudo-WT guts (F and F′) (Df(1)R194, w/hsflp, actGal4, UAS CD8GFP; FRT40, tubGal80, P[RpL36+w+]/FRT40) stained for Dl (red). The arrows indicate a multicellular clone devoid of Dl+ cells.(G) Size distribution of clones as in (E) (blue bars; n = 14 clones of two cells or more) and (F) (red bars; n = 17 clones of two cells or more).(H) Bar graphs showing the distribution of clones based on their Dl+ cell content for M−/+ clones in M−/+ guts (n = 30 clones) and for M−/+ clones in WT guts (n = 47 clones). Note the reduction in Dl+ clones for M−/+ clones in a WT background and the appearance of a large fraction of multicellular clones devoid of Dl+ cells.Scale bars represent 50 μm.

Mentions: A second hallmark of cell competition is that it results in fitter cells taking over the tissue at the expense of less fit cells (Morata and Ripoll, 1975). Therefore, we asked whether wild-type and M−/+ cells would reciprocally affect their colonization and clone survival probabilities in this tissue. To address this, we generated M−/+ guts in which we labeled a subset of M−/+ ISCs (and their progeny) while at the same time inducing labeled wild-type ISCs (Figures 2A and 2B). We then compared clone survival frequencies between the two genotypes at 9 and 15 days after clone induction (ACI; expressed as a fraction of the average number of clones observed 4 days ACI). We also compared the survival frequency of competing M−/+ clones to that of neutral M−/+ clones (in wholly M−/+ guts). As shown in Figure 2C, the survival frequency of M−/+ clones was markedly lower than that of wild-type clones in the same guts, showing clonal disadvantage. Importantly, it was also lower than that of neutral M−/+ clones, indicating that the presence of wild-type clones negatively impacts on the survival probability of competing M−/+ cells. Consistently, this was also accompanied by a trend toward M−/+ clone attrition under competing conditions (Figure 2D).


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)

Wild-Type Cells Induce Clonal Extinction and Stem Cell Loss in M−/+ Tissues(A–D) Independently labeled M−/+ and WT clones were induced in M−/+ guts and their fate was analyzed at 4 (A–A″′, C, and D), 9 (C and D), and 15 (B–B″′, C, and D) days ACI. WT clones are GFP−, whereas M−/+ cells are GFP+. A simultaneous but independent recombination event marks clones by 0×RFP (red fluorescent protein) in an otherwise 1×RFP or 2×RFP tissue, allowing lineage tracing in M−/+ (and in WT) tissue (hsflp; FRT40, ubiRFP/FRT40; FRT82B, ubiGFP, RpS3/FRT82B).(C) Diagram showing the evolution of clone number (expressed as a fraction of the average clone number at 4 days) for WT clones competing in M−/+ tissue (n = 78, 78, and 101 clones at 4, 9, and 15 days ACI, respectively), competing M−/+ clones (0×RFP) from the same guts (genotype as in A) (n = 96, 73, and 45 clones at 4, 9, and 15 days ACI, respectively), and neutral M−/+ clones (0×RFP) in wholly M−/+ guts (hsflp; FRT40, ubiRFP/FRT40; FRT82B, ubiGFP, RpS3/TM2) (n = 142, 41, and 65 clones at 4, 9, and 15 days ACI, respectively).(D) Evolution of median clone size (genotypes and datasets are as in C).(C and D) ∗p < 0.05, ∗∗p < 0.02, Mann-Whitney test. Error bars represent SEM.(E–F′) Six-day-old GFP+M−/+ clones (green) in control M−/+ guts (E and E′) (Df(1)R194, w/hsflp, actGal4, UAS CD8GFP; FRT40, tubGal80/FRT40) or in pseudo-WT guts (F and F′) (Df(1)R194, w/hsflp, actGal4, UAS CD8GFP; FRT40, tubGal80, P[RpL36+w+]/FRT40) stained for Dl (red). The arrows indicate a multicellular clone devoid of Dl+ cells.(G) Size distribution of clones as in (E) (blue bars; n = 14 clones of two cells or more) and (F) (red bars; n = 17 clones of two cells or more).(H) Bar graphs showing the distribution of clones based on their Dl+ cell content for M−/+ clones in M−/+ guts (n = 30 clones) and for M−/+ clones in WT guts (n = 47 clones). Note the reduction in Dl+ clones for M−/+ clones in a WT background and the appearance of a large fraction of multicellular clones devoid of Dl+ cells.Scale bars represent 50 μm.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4537514&req=5

fig2: Wild-Type Cells Induce Clonal Extinction and Stem Cell Loss in M−/+ Tissues(A–D) Independently labeled M−/+ and WT clones were induced in M−/+ guts and their fate was analyzed at 4 (A–A″′, C, and D), 9 (C and D), and 15 (B–B″′, C, and D) days ACI. WT clones are GFP−, whereas M−/+ cells are GFP+. A simultaneous but independent recombination event marks clones by 0×RFP (red fluorescent protein) in an otherwise 1×RFP or 2×RFP tissue, allowing lineage tracing in M−/+ (and in WT) tissue (hsflp; FRT40, ubiRFP/FRT40; FRT82B, ubiGFP, RpS3/FRT82B).(C) Diagram showing the evolution of clone number (expressed as a fraction of the average clone number at 4 days) for WT clones competing in M−/+ tissue (n = 78, 78, and 101 clones at 4, 9, and 15 days ACI, respectively), competing M−/+ clones (0×RFP) from the same guts (genotype as in A) (n = 96, 73, and 45 clones at 4, 9, and 15 days ACI, respectively), and neutral M−/+ clones (0×RFP) in wholly M−/+ guts (hsflp; FRT40, ubiRFP/FRT40; FRT82B, ubiGFP, RpS3/TM2) (n = 142, 41, and 65 clones at 4, 9, and 15 days ACI, respectively).(D) Evolution of median clone size (genotypes and datasets are as in C).(C and D) ∗p < 0.05, ∗∗p < 0.02, Mann-Whitney test. Error bars represent SEM.(E–F′) Six-day-old GFP+M−/+ clones (green) in control M−/+ guts (E and E′) (Df(1)R194, w/hsflp, actGal4, UAS CD8GFP; FRT40, tubGal80/FRT40) or in pseudo-WT guts (F and F′) (Df(1)R194, w/hsflp, actGal4, UAS CD8GFP; FRT40, tubGal80, P[RpL36+w+]/FRT40) stained for Dl (red). The arrows indicate a multicellular clone devoid of Dl+ cells.(G) Size distribution of clones as in (E) (blue bars; n = 14 clones of two cells or more) and (F) (red bars; n = 17 clones of two cells or more).(H) Bar graphs showing the distribution of clones based on their Dl+ cell content for M−/+ clones in M−/+ guts (n = 30 clones) and for M−/+ clones in WT guts (n = 47 clones). Note the reduction in Dl+ clones for M−/+ clones in a WT background and the appearance of a large fraction of multicellular clones devoid of Dl+ cells.Scale bars represent 50 μm.
Mentions: A second hallmark of cell competition is that it results in fitter cells taking over the tissue at the expense of less fit cells (Morata and Ripoll, 1975). Therefore, we asked whether wild-type and M−/+ cells would reciprocally affect their colonization and clone survival probabilities in this tissue. To address this, we generated M−/+ guts in which we labeled a subset of M−/+ ISCs (and their progeny) while at the same time inducing labeled wild-type ISCs (Figures 2A and 2B). We then compared clone survival frequencies between the two genotypes at 9 and 15 days after clone induction (ACI; expressed as a fraction of the average number of clones observed 4 days ACI). We also compared the survival frequency of competing M−/+ clones to that of neutral M−/+ clones (in wholly M−/+ guts). As shown in Figure 2C, the survival frequency of M−/+ clones was markedly lower than that of wild-type clones in the same guts, showing clonal disadvantage. Importantly, it was also lower than that of neutral M−/+ clones, indicating that the presence of wild-type clones negatively impacts on the survival probability of competing M−/+ cells. Consistently, this was also accompanied by a trend toward M−/+ clone attrition under competing conditions (Figure 2D).

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