Chronic activation of JNK JAK/STAT and oxidative stress signalling causes the loser cell status

Kuciński, Iwo; Dinan, Michael; Kolahgar, Golnar; Piddini, Eugenia

doi:10.1038/s41467-017-00145-y

Cited by 113 publications

(153 citation statements)

References 78 publications

(156 reference statements)

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“…Interestingly, mtDNA genes are amongst the top mis-regulated factors identified during cell competition in the mouse skin (Ellis et al, 2019). In the Drosophila wing disc oxidative stress, a general consequence of dysfunctional mitochondria, underlies the out-competition of Minute and Mah-jong mutant cells (Kucinski et al, 2017). Similarly, in Madin-Darby Canine Kidney (MDCK) cells, a loss of Δψm occurs during the out-competition of RasV12 mutant cells and is key for their extrusion (Kon et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development

Lima

Lubatti

Burgstaller

et al. 2020

Preprint

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Cell competition is emerging as a quality control mechanism that eliminates unfit cells in a wide range of settings from development to the adult. However, the nature of the cells normally eliminated by cell competition and what triggers their elimination remains poorly understood. Here we have performed single cell transcriptional profiling of early mouse embryos and find that the cells eliminated show the hallmarks of cell competition, are mis-patterned and have mitochondrial defects. We demonstrate that mitochondrial defects are common to a range of different loser cell types and that manipulating mitochondrial function is sufficient to trigger competition. Importantly, we show that in the embryo loser epiblast cells display mitochondrial DNA mutations and that even small changes in mitochondrial DNA sequence can influence the competitive ability of the cell.Our results therefore suggest that cell competition is a purifying selection that optimises metabolic output prior to gastrulation. Running title: Cell competition and mitochondrial selectionDuring the early stages of mammalian development, the cellular and molecular landscape is 2 profoundly remodelled. As embryonic cells approach gastrulation, when the precursors of all 3 embryonic tissues are specified, they need to rewire the transcriptional, epigenetic, metabolic and 4 signalling networks that govern cell identity (Kojima et al., 2014). These changes are accompanied 5 by a marked acceleration in the proliferation rate (Snow, 1977) and need to be orchestrated with 6 the different morphogenetic processes that re-shape the embryo (reviewed in (Stower and 7 Srinivas, 2018). The scale of this remodelling creates the potential for the emergence of abnormal 8 cells that need to be removed to prevent them from contributing to the soma or germline during 9 development. This requirement implies that there must be stringent cell fitness quality control 10 mechanisms acting around the time of gastrulation. One such control has been postulated to be 11 cell competition, a fitness sensing mechanism eliminating cells that, although viable, are less fit 12 than their neighbours (reviewed in (Bowling et al., 2019; Diaz-Diaz and Torres, 2019; Madan et 13 al., 2018). During cell competition, the cells that are eliminated are generically termed losers, while 14 the fitter cells that survive are referred to as winners. 15Cell competition has been primarily studied in Drosophila, where it was first described in the cell RNA sequencing (scRNA-seq). To ensure we can capture the eliminated cells, as we have 70 done before (Bowling et al., 2018), we isolated embryos at E5.5 and cultured them for 16 hours in 71 the presence of a caspase inhibitors (CI) or vehicle (DMSO) ( Figure 1A and Figure S1A). 72Unsupervised clustering of the scRNA-seq data revealed five clusters: two corresponding to extra-73 embryonic tissues (visceral endoderm and extra-embryonic ectoderm) and three that expressed 74 epiblast marker genes (Figure 1B-C and Figure S1B-D). Interestingly, cells from CI...

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Section: Discussionmentioning

confidence: 99%

Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development

Lima

Lubatti

Burgstaller

et al. 2020

Preprint

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“…p53 is required to induce xrp1 upon irradiation (Akdemir et al, 2007) and was more recently shown to control growth coordination between compartments (Mesquita et al, 2010). In addition, previous work has shown that xrp1 could respond to oxidative stress (Gruenewald et al, 2009), and that both oxidative stress and Nrf2 are linked to Minute-induced cell competition (Kucinski et al, 2017). However, we find that RNAimediated downregulation of p53 or inhibition of oxidative stress signaling (UAS-CAT+SOD, UAS-nrf2 RNAi ) in slow-growing discs produces no or only minor rescue of non-autonomous growth ( Figure S2B).…”

Section: A Role For the Atypical Ribosomal Protein Rps12 In Iocmentioning

confidence: 99%

Inter-Organ Growth Coordination Is Mediated by the Xrp1-Dilp8 Axis in Drosophila

et al. 2019

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How organs scale with other body parts is not mechanistically understood. We have addressed this question using the Drosophila imaginal disc model. When growth of one disc domain is perturbed, other parts of the disc and other discs slow down their growth, maintaining proper inter-disc and intra-disc proportions. We show here that the relaxin-like Dilp8 is required for this inter-organ coordination. Our work also reveals that the stress-response transcription factor Xrp1 plays a key role upstream of dilp8 in linking organ growth status with non-autonomous/systemic growth response. In addition, we show that the small ribosomal subunit protein RpS12 is required to trigger Xrp1-dependent non-autonomous response. Our work demonstrates that RpS12, Xrp1 and Dilp8 constitute an independent regulatory module that ensures intra-and inter-organ growth coordination during development.

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“…The genes upregulated after inactivation of the SAC also include a number encoding proteins involved in the xenobiotic response (CLEMENTE-RUIZ et al 2016). Intriguing, oxidative stress also induces many of these genes (MISRA et al 2011;KUCINSKI et al 2017), including both ones with known antioxidant roles and those, like cytochrome p450s, without known roles in this process. Another striking parallel with the data from the Ruvkun lab is the role of the JNK pathway.…”

Section: Centrosome Loss Immunity and Xenobiotic Detoxificationmentioning

confidence: 99%

Centrosome Loss Triggers a Transcriptional Program to Counter Apoptosis-Induced Oxidative Stress

Poulton

McKay

Peifer³

2018

Preprint

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Centrosomes play a critical role in mitotic spindle assembly through their role in microtubule nucleation and bipolar spindle assembly. Loss of centrosomes can impair the ability of some cells to properly conduct mitotic division, leading to chromosomal instability, cell stress, and aneuploidy. Multiple aspects of the cellular response to mitotic error associated with centrosome loss appears to involve activation of JNK signaling. To further characterize the transcriptional effects of centrosome loss, we compared gene expression profiles of wildtype and acentrosomal cells from Drosophila wing imaginal discs. We found elevation of expression of JNK target genes, which we verified at the protein level. Consistent with this, the upregulated gene set showed significant enrichment for the AP1 consensus DNA binding sequence. We also found significant elevation in expression of genes regulating redox balance. Based on those findings, we examined oxidative stress after centrosome loss, revealing that acentrosomal wing cells have significant increases in reactive oxygen species (ROS). We then performed a candidate genetic screen and found that one of the genes upregulated in acentrosomal cells, G6PD, plays an important role in buffering acentrosomal cells against increased ROS and helps protect those cells from cell death. Our data and other recent studies have revealed a complex network of signaling pathways, transcriptional programs, and cellular processes that epithelial cells use to respond to stressors like mitotic errors to help limit cell damage and maintain normal tissue development.

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Chronic activation of JNK JAK/STAT and oxidative stress signalling causes the loser cell status

Cited by 113 publications

References 78 publications

Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development

Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development

Inter-Organ Growth Coordination Is Mediated by the Xrp1-Dilp8 Axis in Drosophila

Centrosome Loss Triggers a Transcriptional Program to Counter Apoptosis-Induced Oxidative Stress

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