Imperial College London

ProfessorTristanRodriguez

Faculty of MedicineNational Heart & Lung Institute

Professor of Cell and Developmental Biology
 
 
 
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Contact

 

+44 (0)20 7594 5448tristan.rodriguez Website

 
 
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Location

 

331ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

64 results found

Frankenberg Garcia J, Rogers A, Mak J, halayko A, Hui C, xu B, Chung KF, Rodriguez T, Michaeloudes C, Bhavsar Pet al., 2022, Mitochondrial transfer regulates bioenergetics in healthy and COPD airway smooth muscle, American Journal of Respiratory Cell and Molecular Biology, Vol: 67, Pages: 471-481, ISSN: 1044-1549

Mitochondrial dysfunction has been reported in chronic obstructive pulmonary disease (COPD). Transfer of mitochondria from mesenchymal stem cells to airway smooth muscle cells (ASMCs) can attenuate oxidative stress-induced mitochondrial damage. It is not known whether mitochondrial transfer can occur between structural cells in the lungs or what role this may have in modulating bioenergetics and cellular function in healthy and COPD airways. Here, we show that ASMCs from both healthy ex-smokers and subjects with COPD can exchange mitochondria, a process that happens, at least partly, via extracellular vesicles. Exposure to cigarette smoke induces mitochondrial dysfunction and leads to an increase in the donation of mitochondria by ASMCs, suggesting that the latter may be a stress response mechanism. Healthy ex-smoker ASMCs that receive mitochondria show increases in mitochondrial biogenesis and respiration and a reduction in cell proliferation, irrespective of whether the mitochondria are transferred from healthy ex-smoker or COPD ASMCs. Our data indicate that mitochondrial transfer between structural cells is a homeostatic mechanism for the regulation of bioenergetics and cellular function within the airways and may represent an endogenous mechanism for reversing the functional consequences of mitochondrial dysfunction in diseases such as COPD.

Journal article

Nichols J, Lima A, Rodriguez T, 2022, Cell competition and the regulative nature of early mammalian development, Cell Stem Cell, Vol: 29, Pages: 1018-1030, ISSN: 1934-5909

The mammalian embryo exhibits a remarkable plasticity that allows it to correct for the presence of aberrant cells, adjust its growth so that its size is in accordance with its developmental stage, or integrate cells of another species to form fully functional organs. Here, we will discuss the contribution that cell competition, a quality control that eliminates viable cells that are less fit than their neighbours, makes to this plasticity. We will do this by reviewing the roles that cell competition plays in the early mammalian embryo and how they contribute to ensure normal development of the embryo.

Journal article

Pernaute B, Pérez-Montero S, Sánchez Nieto JM, Di Gregorio A, Lima A, Lawlor K, Bowling S, Liccardi G, Tomás A, Meier P, Sesaki H, Rutter GA, Barbaric I, Rodríguez TAet al., 2022, DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism., Dev Cell, Vol: 57, Pages: 1316-1330.e7

The changes that drive differentiation facilitate the emergence of abnormal cells that need to be removed before they contribute to further development or the germline. Consequently, in mice in the lead-up to gastrulation, ∼35% of embryonic cells are eliminated. This elimination is caused by hypersensitivity to apoptosis, but how it is regulated is poorly understood. Here, we show that upon exit of naive pluripotency, mouse embryonic stem cells lower their mitochondrial apoptotic threshold, and this increases their sensitivity to cell death. We demonstrate that this enhanced apoptotic response is induced by a decrease in mitochondrial fission due to a reduction in the activity of dynamin-related protein 1 (DRP1). Furthermore, we show that in naive pluripotent cells, DRP1 prevents apoptosis by promoting mitophagy. In contrast, during differentiation, reduced mitophagy levels facilitate apoptosis. Together, these results indicate that during early mammalian development, DRP1 regulation of mitophagy determines the apoptotic response.

Journal article

Georgiadou E, Muralidharan C, Martinez M, Chabosseau P, Akalestou E, Tomas A, Yong Su Wern F, Stylianides T, Wretlind A, Legido-Quigley C, Jones B, Lopez Noriega L, Xu Y, Gu G, Alsabeeh N, Cruciani-Guglielmacci C, Magnan C, Ibberson M, Leclerc I, Ali Y, Soleimanpour SA, Linnemann AK, Rodriguez TA, Rutter GAet al., 2022, Mitofusins Mfn1 and Mfn2 are required to preserve glucose- but not incretin-stimulated beta cell connectivity and insulin secretion, Diabetes, Vol: 71, Pages: 1472-1489, ISSN: 0012-1797

Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic beta cells. Whether mitofusin gene expression, and hence mitochondrial network integrity, is important for glucose or incretin signalling has not previously been explored. Here, we generated mice with beta cell-selective, adult-restricted deletion of the mitofusin genes Mfn1 and Mfn2 (βMfn1/2 dKO). βMfn1/2 dKO mice displayed elevated fed and fasted glycaemia and a >five-fold decrease in plasma insulin. Mitochondrial length, glucose-induced polarisation, ATP synthesis, cytosolic and mitochondrial Ca2+ increases were all reduced in dKO islets. In contrast, oral glucose tolerance was more modestly affected in βMfn1/2 dKO mice and GLP-1 or GIP receptor agonists largely corrected defective GSIS through enhanced EPAC-dependent signalling. Correspondingly, cAMP increases in the cytosol, as measured with an Epac-camps based sensor, were exaggerated in dKO mice. Mitochondrial fusion and fission cycles are thus essential in the beta cell to maintain normal glucose, but not incretin, sensing. These findings broaden our understanding of the roles of mitofusins in beta cells, the potential contributions of altered mitochondrial dynamics to diabetes development and the impact of incretins on this process.

Journal article

Montero SP, Bowling S, Pérez-Carrasco R, Rodriguez TAet al., 2022, Levels of p53 expression determine the competitive ability of embryonic stem cells during the onset of differentiation

<jats:title>ABSTRACT</jats:title><jats:p>During development, the rate of tissue growth is determined by the relative balance of cell division and cell death. Cell competition is a fitness quality control mechanism that contributes to this balance by eliminating viable cells that are less-fit than their neighbours. What mutations confer cells with a competitive advantage or the dynamics of the interactions between winner and loser cells are not well understood. Here, we show that embryonic cells lacking the tumour suppressor <jats:italic>p53</jats:italic> are super-competitors that eliminate their wild-type neighbours through the direct induction of apoptosis. This elimination is context dependant, as does not occur when cells are pluripotent and is triggered by the onset of differentiation. Furthermore, by combining mathematical modelling and cell-based assays we show that the elimination of wild-type cells is not through a competition for space or nutrients, but instead is mediated by short range interactions that are dependent on the local cell neighbourhood. This highlights the importance of the local cell neighbourhood and the competitive interactions within this neighbourhood for the regulation of proliferation during early embryonic development.</jats:p>

Journal article

Lima A, Rodriguez TA, 2021, MHC-I presents: tumor surveillance in the epithelia by cell competition, NATURE IMMUNOLOGY, Vol: 22, Pages: 1358-1360, ISSN: 1529-2908

Journal article

Price CJ, Stavish D, Gokhale PJ, Stevenson BA, Sargeant S, Lacey J, Rodriguez TA, Barbaric Iet al., 2021, Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition, Developmental Cell, Vol: 56, Pages: 2455-2470.e10, 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.

Journal article

Lima A, Rodriguez TA, 2021, DB special issue - Cell Competition in Development and Disease, DEVELOPMENTAL BIOLOGY, Vol: 479, Pages: 123-125, ISSN: 0012-1606

Journal article

Lima A, Lubatti G, Burgstaller J, Hu D, Green AP, Di Gregorio A, Zawadzki T, Pernaute B, Mahammadov E, Perez-Montero S, Dore M, Sanchez JM, Bowling S, Sancho M, Kolbe T, Karimi MM, Carling D, Jones N, Srinivas S, Sciadldone A, Rodriguez Tet 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.

Journal article

Pilley S, Rodriguez TA, Vousden KH, 2021, Mutant p53 in cell-cell interactions, GENES & DEVELOPMENT, Vol: 35, Pages: 433-448, ISSN: 0890-9369

Journal article

Lima A, Rodriguez TA, 2021, Cell Competition: A Choreographed Dance of Death, CURRENT BIOLOGY, Vol: 31, Pages: R255-+, ISSN: 0960-9822

Journal article

Georgiadou E, Muralidharan C, Martinez M, Chabosseau P, Tomas A, Su Wern FY, Akalestou E, Stylianides T, Wretlind A, Legido-Quigley C, Jones B, Noriega LL, Xu Y, Gu G, Alsabeeh N, Cruciani-Guglielmacci C, Magnan C, Ibberson M, Leclerc I, Ali Y, Soleimanpour SA, Linnemann AK, Rodriguez TA, Rutter GAet 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&lt;0.01, p&lt;0.001) and a &gt;five-fold decrease (p&lt;0.0001) in plasma insulin. Mitochondrial length, glucose-induced polarisation, ATP synthesis and cytosolic Ca2+ increases were all reduced (p&lt;0.05,p&lt;0.01,p&lt;0.0001) in dKO islets, and beta cell Ca2+ dynamics were suppressed in vivo (p&lt;0.001). In contrast, oral glucose tolerance was near normal in βMfn1/2 dKO mice (p&lt;0.05, p&lt;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

Journal article

Lawlor K, Marques-Torrejon MA, Dharmalingham G, El-Azhar Y, Schneider M, Pollard S, Rodríguez T, Rodriguez Tet 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.

Journal article

Roman-Trufero M, Ito CM, Pedebos C, Magdalou I, Wang Y-F, Karimi MM, Moyon B, Webster Z, di Gregorio A, Azuara V, Khalid S, Speck C, Rodriguez T, Dillon Net 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.

Journal article

Lawlor K, Perez Montero S, Lima A, Rodriguez Tet 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.

Journal article

Roman-Trufero M, Ito CM, Pedebos C, Magdalou I, Wang Y-F, Karimi MM, Moyon B, Webster Z, Gregorio AD, Azuara V, Khalid S, Speck C, Rodriguez T, Dillon Net 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>

Journal article

Lima A, Lubatti G, Burgstaller J, Hu D, Green A, Gregorio AD, Zawadzki T, Pernaute B, Mahammadov E, Montero SP, Dore M, Sanchez JM, Bowling S, Sancho M, Karimi M, Carling D, Jones N, Srinivas S, Scialdone A, Rodriguez TAet al., 2020, Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development

<jats:title>Abstract</jats:title><jats:p>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 mouse, prior to gastrulation 35% of epiblast cells are eliminated. Here we have performed single cell transcriptional profiling of these cells and find that they show the hallmarks of cell competition 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 cell competition eliminates cells with mitochondrial DNA mutations and that even non-pathological changes in mitochondrial DNA sequence can induce cell competition. Our results therefore suggest that cell competition is a purifying selection that optimises mitochondrial performance prior to gastrulation.</jats:p>

Journal article

Pozzi S, Bowling S, Apps J, Brickman JM, Rodriguez TA, Martinez-Barbera JPet 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

Journal article

Lawlor K, Marques-Torrejon MA, Dharmalingham G, El-Azhar Y, Schneider M, Pollard S, Rodríguez Tet 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.

Working paper

Price CJ, Stavish D, Gokhale PJ, Sargeant S, Lacey J, Rodriguez TA, Barbaric Iet al., 2019, Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition

<jats:title>Abstract</jats:title><jats:p>The appearance of genetic changes in human pluripotent stem cells (hPSCs) presents a concern for their use in research and regenerative medicine. Variant hPSCs harbouring recurrent culture-acquired aneuploidies display growth advantages over wild-type diploid cells, but the mechanisms yielding 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 resulting in 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 YAP in the cytoplasm that induces apoptosis in wild-type cells. Importantly, YAP overexpression in wild-type cells is sufficient to alleviate their loser phenotype. Our results demonstrate that hPSC fate is coupled to mechanical cues imposed by neighbouring cells and reveal that hijacking this mechanism allows variants to achieve clonal dominance in cultures.</jats:p>

Journal article

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.

Journal article

Pernaute B, Sánchez Nieto JM, Pérez-Montero S, di Gregorio A, Lima A, Lawlor K, Bowling S, Liccardi G, Tomás A, Meier P, Rutter GA, Barbaric I, Rodríguez TAet al., 2019, DRP1-mediated regulation of mitochondrial dynamics determines the apoptotic response upon embryonic differentiation, bioRxiv

The changes that drive differentiation create a large potential for the emergence of abnormal cells that need to be removed before they contribute to further development or the germline. This removal is in part achieved by cells becoming hypersensitive to death upon exit of naïve pluripotency. What causes this change in apoptotic response is unknown. Here we identify that it is controlled by the regulator of mitochondrial dynamics DRP1. We show that in mouse, naïve pluripotent cells have fragmented mitochondria due to high DRP1-mediated fission, but upon differentiation, DRP1 activity decreases, inducing mitochondria to fuse and form complex networks. We demonstrate that this decrease in DRP1 activity lowers the apoptotic threshold, as mutation of DRP1 increases the sensitivity to cell death and its over-expression protects against apoptosis. Together, our findings highlight how regulation of mitochondrial dynamics allows cells to adapt their apoptotic response to the changing environment of differentiation.

Journal article

Bowling S, Di Gregorio A, Sancho M, Pozzi S, Aarts M, Signore M, Schneider MD, Martinez-Barbera JP, Gil J, Rodriguez TAet 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.

Journal article

Bowling S, Di Gregorio A, Sancho M, Pozzi S, Aarts M, Signore M, Schneider M, Martinez Barbera JP, Gil J, Rodriguez TAet 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.

Journal article

Lima A, Burgstaller J, Sanchez Nieto JM, Rodriguez Tet 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.

Journal article

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.

Journal article

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

Journal article

Gil J, Rodriguez T, 2016, Cancer: The Transforming Power of Cell Competition, CURRENT BIOLOGY, Vol: 26, Pages: R164-R166, ISSN: 0960-9822

Journal article

Arber C, Precious SV, Cambray S, Risner-Janiczek JR, Kelly C, Noakes Z, Fjodorova M, Heuer A, Ungless MA, Rodriguez TA, Rosser AE, Dunnett SB, Li Met al., 2015, Activin A directs striatal projection neuron differentiation of human pluripotent stem cells, DEVELOPMENT, Vol: 142, Pages: 1375-1386, ISSN: 0950-1991

Journal article

Peltzer N, Rieser E, Taraborrelli L, Draber P, Darding M, Pemaute B, Shimizu Y, Sarr A, Draberova H, Montinaro A, Martinez-Barbera JP, Silke J, Rodriguez TA, Walczak Het 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.

Journal article

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