53 results found
Price CJ, Stavish D, Gokhale PJ, et al., 2021, Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition, Developmental Cell, ISSN: 1534-5807
The appearance of genetic changes in human pluripotent stem cells (hPSCs) presents a concern for their use in research and regenerative medicine. Variant hPSCs that harbor recurrent culture-acquired aneuploidies display growth advantages over wild-type diploid cells, but the mechanisms that yield a drift from predominantly wild-type to variant cell populations remain poorly understood. Here, we show that the dominance of variant clones in mosaic cultures is enhanced through competitive interactions that result in the elimination of wild-type cells. This elimination occurs through corralling and mechanical compression by faster-growing variants, causing a redistribution of F-actin and sequestration of yes-associated protein (YAP) in the cytoplasm that induces apoptosis in wild-type cells. YAP overexpression or promotion of YAP nuclear localization in wild-type cells alleviates their "loser" phenotype. Our results demonstrate that hPSC fate is coupled to mechanical cues imposed by neighboring cells and reveal that hijacking this mechanism allows variants to achieve clonal dominance in cultures.
Lima A, Lubatti G, Burgstaller J, et al., 2021, Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development, Nature Metabolism, Vol: 3, Pages: 1091-1108, ISSN: 2522-5812
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. In mice, 35% of epiblast cells are eliminated prior to gastrulation. Here we show that cells with mitochondrial defects are eliminated by cell competition during early mouse development. Using single cell transcriptional profiling of eliminated mouse epiblast cells we identify hallmarks of cell competition and mitochondrial defects. We go on to demonstrate that mitochondrial defects are common to a range of different loser cell types and that manipulating mitochondrial function triggers cell competition. In the mouse embryo, cell competition eliminates cells with sequence changes in mt-Rnr1 and mt-Rnr2, and that even non-pathological changes in mitochondrial DNA sequence can induce cell competition. Our results suggest that cell competition is a purifying selection that optimises mitochondrial performance prior to gastrulation.
Pilley S, Rodriguez TA, Vousden KH, 2021, Mutant p53 in cell-cell interactions, GENES & DEVELOPMENT, Vol: 35, Pages: 433-448, ISSN: 0890-9369
Georgiadou E, Muralidharan C, Martinez M, et al., 2021, Mitofusins Mfn1 and Mfn2 are required to preserve glucose-but not incretin- stimulated beta cell connectivity and insulin secretion, bioRxiv
Aims/hypothesis Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic beta cells. Whether mitochondrial networks may be important for glucose or incretin sensing has yet to be determined.Methods Here, we generated mice with beta cell-selective, adult-restricted deletion of the mitofusin genes Mfn1 and Mfn2 (βMfn1/2 dKO). Whole or dissociated pancreatic islets were used for live beta cell fluorescence imaging of cytosolic or mitochondrial Ca2+ concentration and ATP production or GSIS in response to increasing glucose concentrations or GLP-1 receptor agonists. Serum and blood samples were collected to examine oral and i.p. glucose tolerance.Results βMfn1/2 dKO mice displayed elevated fed and fasted glycaemia (p<0.01, p<0.001) and a >five-fold decrease (p<0.0001) in plasma insulin. Mitochondrial length, glucose-induced polarisation, ATP synthesis and cytosolic Ca2+ increases were all reduced (p<0.05,p<0.01,p<0.0001) in dKO islets, and beta cell Ca2+ dynamics were suppressed in vivo (p<0.001). In contrast, oral glucose tolerance was near normal in βMfn1/2 dKO mice (p<0.05, p<0.01) and GLP-1 or GIP receptor agonists largely corrected defective GSIS from isolated islets through an EPAC-dependent signalling activation.Conclusions/interpretation Mitochondrial fusion and fission cycles are thus essential in the beta cell to maintain normal glucose, but not incretin, sensing. Defects in these cycles in some forms of diabetes might therefore provide opportunities for novel incretin-based or other therapies.Impact of Mfn1/2 deletion on glucose and incretin stimulated-insulin secretion in beta cells. (A) In control animals, glucose is taken up by beta cells through GLUT2 and metabolised by mitochondria (elongated structure) through the citrate (TCA) cycle, leading to an increased mitochondrial proton motive force (hyperpolarised Δψm), accelerated
Lawlor K, Marques-Torrejon MA, Dharmalingham G, et al., 2020, Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signalling, Genes and Development, Vol: 34, Pages: 1599-1604, ISSN: 0890-9369
There is increasing evidence demonstrating that adult neural stem cells (NSCs) are a cell of origin of glioblastoma. Here we analyzed the interaction between transformed and wild-type NSCs isolated from the adult mouse subventricular zone niche. We found that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, we also demonstrated that these cells induce quiescence in surrounding wild-type NSCs in a cell–cell contact and Notch signaling-dependent manner. Our findings therefore suggest that oncogenic mutations are propagated in the stem cell niche not just through cell-intrinsic advantages, but also by outcompeting neighboring stem cells through repression of their proliferation.
Roman-Trufero M, Ito CM, Pedebos C, et al., 2020, Evolution of an amniote-specific mechanism for modulating ubiquitin signalling via phosphoregulation of the E2 enzyme UBE2D3, Molecular Biology and Evolution, Vol: 37, Pages: 1986-2001, ISSN: 0737-4038
Genetic variation in the enzymes that catalyse post-translational modification of proteins is a potentially important source of phenotypic variation during evolution. Ubiquitination is one such modification that affects turnover of virtually all of the proteins in the cell in addition to roles in signalling and epigenetic regulation. UBE2D3 is a promiscuous E2 enzyme, which acts as a ubiquitin donor for E3 ligases that catalyse ubiquitination of developmentally important proteins. We have used protein sequence comparison of UBE2D3 orthologues to identify a position in the C-terminal α-helical region of UBE2D3 that is occupied by a conserved serine in amniotes and by alanine in anamniote vertebrate and invertebrate lineages. Acquisition of the serine (S138) in the common ancestor to modern amniotes created a phosphorylation site for Aurora B. Phosphorylation of S138 disrupts the structure of UBE2D3 and reduces the level of the protein in mouse ES cells (ESCs). Substitution of S138 with the anamniote alanine (S138A) increases the level of UBE2D3 in ESCs as well as being a gain of function early embryonic lethal mutation in mice. When mutant S138A ESCs were differentiated into extra-embryonic primitive endoderm (PrE), levels of the PDGFRα and FGFR1 receptor tyrosine kinases (RTKs) were reduced and PreE differentiation was compromised. Proximity ligation analysis showed increased interaction between UBE2D3 and the E3 ligase CBL and between CBL and the RTKs. Our results identify a sequence change that altered the ubiquitination landscape at the base of the amniote lineage with potential effects on amniote biology and evolution.
Lawlor K, Perez Montero S, Lima A, et al., 2020, Transcriptional versus metabolic control of cell fitness during cell competition, Seminars in Cancer Biology, Vol: 63, Pages: 36-43, ISSN: 1044-579X
The maintenance of tissue homeostasis and health relies on the efficient removal of damaged or otherwise suboptimal cells. One way this is achieved is through cell competition, a fitness quality control mechanism that eliminates cells that are less fit than their neighbours. Through this process, cell competition has been shown to play diverse roles in development and in the adult, including in homeostasis and tumour suppression. However, over the last few years it has also become apparent that certain oncogenic mutations can provide cells with a competitive advantage that promotes their expansion via the elimination of surrounding wild-type cells. Thus, understanding how this process is initiated and regulated will provide important insights with relevance to a number of different research areas. A key question in cell competition is what determines the competitive fitness of a cell. Here, we will review what is known about this question by focussing on two non-mutually exclusive possibilities; first, that the activity of a subset of transcription factors determines competitive fitness, and second, that the outcome of cell competition is determined by the relative cellular metabolic status.
Roman-Trufero M, Ito CM, Pedebos C, et al., 2020, Evolution of an amniote-specific mechanism for modulating ubiquitin signalling via phosphoregulation of the E2 enzyme UBE2D3, Molecular Biology and Evolution, ISSN: 0737-4038
<jats:title>Abstract</jats:title><jats:p>Genetic variation in the enzymes that catalyse post-translational modification of proteins is a potentially important source of phenotypic variation during evolution. Ubiquitination is one such modification that affects turnover of virtually all of the proteins in the cell in addition to roles in signalling and epigenetic regulation. UBE2D3 is a promiscuous E2 enzyme that acts as a ubiquitin donor for E3 ligases that catalyse ubiquitination of developmentally important proteins. We have used protein sequence comparison of UBE2D3 orthologues to identify a position in the C-terminal α-helical region of UBE2D3 that is occupied by a conserved serine in amniotes and by alanine in anamniote vertebrate and invertebrate lineages. Acquisition of the serine (S138) in the common ancestor to modern amniotes created a phosphorylation site for Aurora B. Phosphorylation of S138 disrupts the structure of UBE2D3 and reduces the level of the protein in mouse ES cells (ESCs). Substitution of S138 with the anamniote alanine (S138A) increases the level of UBE2D3 in ESCs as well as being a gain of function early embryonic lethal in mice. When mutant S138A ESCs were differentiated into extra-embryonic primitive endoderm (PrE), levels of the PDGFRα and FGFR1 receptor tyrosine kinases (RTKs) were reduced and PreE differentiation was compromised. Proximity ligation analysis showed increased interaction between UBE2D3 and the E3 ligase CBL and between CBL and the RTKs. Our results identify a sequence change that altered the ubiquitination landscape at the base of the amniote lineage with potential effects on amniote biology and evolution.</jats:p>
Pozzi S, Bowling S, Apps J, et al., 2019, Genetic Deletion of Hesx1 Promotes Exit from the Pluripotent State and Impairs Developmental Diapause, STEM CELL REPORTS, Vol: 13, Pages: 970-979, ISSN: 2213-6711
Lawlor K, Marques-Torrejon MA, Dharmalingham G, et al., 2019, Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signalling, Publisher: bioRxiv
Abstract There is increasing evidence suggesting that adult neural stem cells (NSCs) are a cell of origin of glioblastoma, the most aggressive form of malignant glioma. The earliest stages of hyperplasia are not easy to explore, but likely involve a cross-talk between normal and transformed NSCs. How normal cells respond to this cross-talk and if they expand or are outcompeted is poorly understood. Here we have analysed the interaction of transformed and wild-type NSCs isolated from the adult mouse subventricular zone neural stem cell niche. We find that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, however, we also demonstrate that these cells induce a quiescent-like state in surrounding wild-type NSC. We find that this response is cell-cell contact-dependent and that transformed cells activate the Notch pathway in adjacent wild-type NSCs, an event that stimulates their entry into quiescence. Our findings therefore suggest that oncogenic mutations may be propagated in the stem cell niche not just though cell-intrinsic advantages, but also by outcompeting neighbouring stem cells through signalling repression of their proliferation.
Bowling S, Lawlor K, Rodriguez T, 2019, Cell competition: The winners and losers of fitness selection, Development, Vol: 146, Pages: 1-12, ISSN: 0950-1991
The process of cell competition results in the elimination of cells that are viable but “less fit” than surrounding cells. Given the highly heterogeneous nature of our tissues, it seems increasingly likely that cells are engaged in a “survival of the fittest” battle throughout life. The process has myriad positive roles in the organism: it selects against mutant cells in developing tissues, prevents the propagation of oncogenic cells, and eliminates damaged cells during ageing. However, “super-fit” cancer cells can exploit cell competition mechanisms to expand and spread. Here, we review the regulation, roles and risks of cell competition in organism development, ageing and disease.
Bowling S, Di Gregorio A, Sancho M, et al., 2018, Author correction: P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development, Nature Communications, Vol: 9, ISSN: 2041-1723
The original version of this Article contained an error in the spelling of Juan Pedro Martinez-Barbera, which was incorrectly given as Juan Pedro Martinez Barbera. This error has now been corrected in both the PDF and HTML versions of the Article.
Bowling S, Di Gregorio A, Sancho M, et al., 2018, P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development, Nature Communications, Vol: 9, ISSN: 2041-1723
Ensuring the fitness of the pluripotent cells that will contribute to future development is important both for the integrity of the germline and for proper embryogenesis. Consequently, it is becoming increasingly apparent that pluripotent cells can compare their fitness levels and signal the elimination of those cells that are less fit than their neighbours. In mammals the nature of the pathways that communicate fitness remain largely unknown. Here we identify that in the early mouse embryo and upon exit from naive pluripotency, the confrontation of cells with different fitness levels leads to an inhibition of mTOR signalling in the less fit cell type, causing its elimination. We show that during this process, p53 acts upstream of mTOR and is required to repress its activity. Finally, we demonstrate that during normal development around 35% of cells are eliminated by this pathway, highlighting the importance of this mechanism for embryonic development.
Lima A, Burgstaller J, Sanchez Nieto JM, et al., 2017, The mitochondria and the regulation of cell fitness during earlymammalian development, Current Topics in Developmental Biology, Vol: 128, Pages: 339-363, ISSN: 0070-2153
From fertilization until the onset of gastrulation the early mammalian embryo undergoes a dramatic series of changes that converts a single fertilized cell into a remarkably complex organism. Much attention has been given to the molecular changes occurring during this process, but here we will review what is known about the changes affecting the mitochondria and how they impact on the energy metabolism and apoptotic response of the embryo. We will also focus on understanding what quality control mechanisms ensure optimal mitochondrial activity in the embryo, and in this way provide an overview of the importance of the mitochondria in determining cell fitness during early mammalian development.
Srinivas S, Rodriguez TA, 2017, A tale of division and polarization in the mammalian embryo, Developmental Cell, Vol: 40, Pages: 215-216, ISSN: 1534-5807
The first cell fate choice in mouse development is the segregation of the embryonic inner cell mass and the extra-embryonic trophectoderm. In this issue of Developmental Cell, Korotkevic and colleagues (2017) show that the interplay between cell polarization and cell-cell contact drives the segregation of these lineages, providing a framework for self-organization in development.
di gregorio A, Bowling S, Rodriguez T, 2016, Cell Competition and its role in the regulation of cell fitness from development to cancer, Developmental Cell, Vol: 38, Pages: 621-634, ISSN: 1878-1551
Cell competition is a cell fitness-sensing mechanism conserved from insects to mammals that eliminatesthose cells that, although viable, are less fit than their neighbors. An important implication of cell competitionis that cellular fitness is not only a cell-intrinsic property but is also determined relative to the fitness ofneighboring cells: a cell that is of suboptimal fitness in one context may be ‘‘super-fit’’ in the context of adifferent cell population. Here we discuss the mechanisms by which cell competition measures and communicatescell fitness levels and the implications of this mechanism for development, regeneration, and tumorprogression
Gil J, Rodriguez T, 2016, Cancer: The Transforming Power of Cell Competition, CURRENT BIOLOGY, Vol: 26, Pages: R164-R166, ISSN: 0960-9822
Arber C, Precious SV, Cambray S, et al., 2015, Activin A directs striatal projection neuron differentiation of human pluripotent stem cells, DEVELOPMENT, Vol: 142, Pages: 1375-1386, ISSN: 0950-1991
Peltzer N, Rieser E, Taraborrelli L, et al., 2014, HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death, Cell Reports, Vol: 9, Pages: 153-165, ISSN: 2211-1247
Linear ubiquitination is crucial for innate and adaptive immunity. The linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP, and SHARPIN, is the only known ubiquitin ligase that generates linear ubiquitin linkages. HOIP is the catalytically active LUBAC component. Here, we show that both constitutive and Tie2-Cre-driven HOIP deletion lead to aberrant endothelial cell death, resulting in defective vascularization and embryonic lethality at midgestation. Ablation of tumor necrosis factor receptor 1 (TNFR1) prevents cell death, vascularization defects, and death at midgestation. HOIP-deficient cells are more sensitive to death induction by both tumor necrosis factor (TNF) and lymphotoxin-α (LT-α), and aberrant complex-II formation is responsible for sensitization to TNFR1-mediated cell death in the absence of HOIP. Finally, we show that HOIP’s catalytic activity is necessary for preventing TNF-induced cell death. Hence, LUBAC and its linear-ubiquitin-forming activity are required for maintaining vascular integrity during embryogenesis by preventing TNFR1-mediated endothelial cell death.
Pernaute B, Spruce T, Smith KM, et al., 2014, MicroRNAs control the apoptotic threshold in primed Pluripotent stem cells through regulation of BIM, Genes and Development, Vol: 28, Pages: 1873-1878, ISSN: 0890-9369
Mammalian primed pluripotent stem cells have been shown to be highly susceptible to cell death stimuli due to their low apoptotic threshold, but how this threshold is regulated remains largely unknown. Here we identify microRNA (miRNA)-mediated regulation as a key mechanism controlling apoptosis in the post-implantation epiblast. Moreover, we found that three miRNA families, miR-20, miR-92, and miR-302, control the mitochondrial apoptotic machinery by fine-tuning the levels of expression of the proapoptotic protein BIM. These families therefore represent an essential buffer needed to maintain cell survival in stem cells that are primed for not only differentiation but also cell death.
Arber C, Precious SV, Cambray S, et al., 2014, Directing striatal GABAergic fate specification of human pluripotent stem cells, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 145-146, ISSN: 0959-4965
Sancho M, Rodriguez TA, 2014, Selecting for fitness in mammalian development, CELL CYCLE, Vol: 13, Pages: 9-10, ISSN: 1538-4101
Sancho M, Rodriguez TA, 2013, Ready, set, differentiate!, eLife, Vol: 2, ISSN: 2050-084X
The expression of E-Cadherin, a protein best known for its role in cell adhesion, regulates the onset of embryonic differentiation.
Sancho M, Di-Gregorio A, George N, et al., 2013, Competitive Interactions Eliminate Unfit Embryonic Stem Cells at the Onset of Differentiation, DEVELOPMENTAL CELL, Vol: 26, Pages: 19-30, ISSN: 1534-5807
Manzanares M, Rodriguez TA, 2013, Development: Hippo Signalling Turns the Embryo Inside Out, CURRENT BIOLOGY, Vol: 23, Pages: R559-R561, ISSN: 0960-9822
Cambray S, Arber C, Little G, et al., 2012, Activin induces cortical interneuron identity and differentiation in embryonic stem cell-derived telencephalic neural precursors, NATURE COMMUNICATIONS, Vol: 3, ISSN: 2041-1723
Trichas G, Smith AM, White N, et al., 2012, Multi-Cellular Rosettes in the Mouse Visceral Endoderm Facilitate the Ordered Migration of Anterior Visceral Endoderm Cells, PLOS BIOLOGY, Vol: 10, ISSN: 1544-9173
Paca A, Seguin CA, Clements M, et al., 2012, BMP signaling induces visceral endoderm differentiation of XEN cells and parietal endoderm, DEVELOPMENTAL BIOLOGY, Vol: 361, Pages: 90-102, ISSN: 0012-1606
Clements M, Pernaute B, Vella F, et al., 2011, Crosstalk between Nodal/Activin and MAPK p38 Signaling Is Essential for Anterior-Posterior Axis Specification, CURRENT BIOLOGY, Vol: 21, Pages: 1289-1295, ISSN: 0960-9822
Stuckey DW, Clements M, Di-Gregorio A, et al., 2011, Coordination of cell proliferation and anterior-posterior axis establishment in the mouse embryo, Development, Vol: 138, Pages: 1521-1530
During development, the growth of the embryo must be coupled to its patterning to ensure correct and timely morphogenesis.In the mouse embryo, migration of the anterior visceral endoderm (AVE) to the prospective anterior establishes the anteriorposterior(A-P) axis. By analysing the distribution of cells in S phase, M phase and G2 from the time just prior to the migration ofthe AVE until 18 hours after its movement, we show that there is no evidence for differential proliferation along the A-P axis ofthe mouse embryo. Rather, we have identified that as AVE movements are being initiated, the epiblast proliferates at a muchhigher rate than the visceral endoderm. We show that these high levels of proliferation in the epiblast are dependent on Nodalsignalling and are required for A-P establishment, as blocking cell division in the epiblast inhibits AVE migration. Interestingly,inhibition of migration by blocking proliferation can be rescued by Dkk1. This suggests that the high levels of epiblastproliferation function to move the prospective AVE away from signals that are inhibitory to its migration. The finding thatinitiation of AVE movements requires a certain level of proliferation in the epiblast provides a mechanism whereby A-P axisdevelopment is coordinated with embryonic growth.
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