Imperial College London

DR MICHALIS BARKOULAS

Faculty of Natural SciencesDepartment of Life Sciences

Senior Lecturer
 
 
 
//

Contact

 

+44 (0)20 7594 5227m.barkoulas

 
 
//

Location

 

607Sir Alexander Fleming BuildingSouth Kensington Campus

//

Summary

 

Publications

Publication Type
Year
to

25 results found

Hintze M, Koneru SL, Gilbert SPR, Katsanos D, Barkoulas Met al., 2019, A cell fate switch in the C. elegans seam cell lineage occurs through modulation of the Wnt asymmetry pathway in response to temperature increase

<jats:title>Abstract</jats:title><jats:p>Populations often display consistent developmental phenotypes across individuals despite the inevitable biological stochasticity. Nevertheless, developmental robustness has limits and systems can fail upon change in the environment or the genetic background. We use here the seam cells, a population of epidermal stem cells in <jats:italic>Caenorhabditis elegans</jats:italic>, to study the influence of temperature change and genetic variation on cell fate. Seam cell development has mostly been studied so far in the lab reference strain (N2), grown at 20° temperature. We demonstrate that an increase in culture temperature to 25°, introduces variability in the wild-type seam cell lineage with a proportion of animals showing an increase in seam cell number. We map this increase to lineage-specific symmetrisation events of normally asymmetric cell divisions at the final larval stage, leading to the retention of seam cell fate in both daughter cells. Using genetics and single molecule imaging, we demonstrate that this symmetrisation occurs via changes in the Wnt asymmetry pathway, leading to aberrant Wnt target activation in anterior cell daughters. We find that intrinsic differences in the Wnt asymmetry pathway already exist between seam cells at 20° and this may sensitise cells towards a cell fate switch at increased temperature. Finally, we demonstrate that wild isolates of <jats:italic>C. elegans</jats:italic> display variation in seam cell sensitivity to increased culture temperature, although seam cell numbers are comparable when raised at 20°. Our results highlight how temperature can modulate cell fate decisions in an invertebrate model of stem cell patterning.</jats:p>

Journal article

Reddy KC, Dror T, Underwood RS, Osman GA, Elder CR, Desjardins CA, Cuomo CA, Barkoulas M, Troemel ERet al., 2019, Antagonistic paralogs control a switch between growth and pathogen resistance in C. elegans, PLOS PATHOGENS, Vol: 15, ISSN: 1553-7366

Journal article

Barkoulas M, Osman G, Fasseas M, Koneru S, Kyrou Ket al., 2018, Natural infection of C. elegans by an oomycete reveals a new pathogen-specific immune response, Current Biology, Vol: 28, Pages: 640-648.e5, ISSN: 1879-0445

In its natural habitat, the nematode Caenorhabditis elegans encounters a plethora of other organisms, including many that are pathogenic [ 1 ; 2]. The study of interactions between C. elegans and various pathogens has contributed to characterizing key mechanisms of innate immunity [ 2; 3 ; 4]. However, how C. elegans recognizes different pathogens to mount pathogen-specific immune responses remains still largely unknown [ 3; 5; 6; 7 ; 8]. Expanding the range of known C. elegans-infecting pathogens and characterizing novel pathogen-specific immune responses are key steps toward answering this question. We report here that the oomycete Myzocytiopsis humicola is a natural pathogen of C. elegans, and we describe its infection strategy. We identify a new host immune response to pathogen exposure that involves induction of members of a previously uncharacterized gene family encoding chitinase-like (CHIL) proteins. We demonstrate that this response is highly specific against M. humicola and antagonizes the infection. We propose that CHIL proteins may diminish the ability of the oomycete to infect by hindering pathogen attachment to the host cuticle. This work expands our knowledge of natural eukaryotic pathogens of C. elegans and introduces a new pathosystem to address how animal hosts recognize and respond to oomycete infections.

Journal article

Katsanos D, Koneru SL, Mestek Boukhibar L, Gritti N, Ghose R, Appleford PJ, Doitsidou M, Woollard A, van Zon JS, Poole RJ, Barkoulas Met al., 2017, Stochastic loss and gain of symmetric divisions in the C. elegans epidermis perturbs robustness of stem cell number., PLoS Biology, Vol: 15, ISSN: 1544-9173

Biological systems are subject to inherent stochasticity. Nevertheless, development is remarkably robust, ensuring the consistency of key phenotypic traits such as correct cell numbers in a certain tissue. It is currently unclear which genes modulate phenotypic variability, what their relationship is to core components of developmental gene networks, and what is the developmental basis of variable phenotypes. Here, we start addressing these questions using the robust number of Caenorhabditis elegans epidermal stem cells, known as seam cells, as a readout. We employ genetics, cell lineage tracing, and single molecule imaging to show that mutations in lin-22, a Hes-related basic helix-loop-helix (bHLH) transcription factor, increase seam cell number variability. We show that the increase in phenotypic variability is due to stochastic conversion of normally symmetric cell divisions to asymmetric and vice versa during development, which affect the terminal seam cell number in opposing directions. We demonstrate that LIN-22 acts within the epidermal gene network to antagonise the Wnt signalling pathway. However, lin-22 mutants exhibit cell-to-cell variability in Wnt pathway activation, which correlates with and may drive phenotypic variability. Our study demonstrates the feasibility to study phenotypic trait variance in tractable model organisms using unbiased mutagenesis screens.

Journal article

Barkoulas M, Vargas Velazquez AM, Peluffo AE, Félix MAet al., 2016, Evolution of New cis-Regulatory Motifs Required for Cell-Specific Gene Expression in Caenorhabditis, PLOS Genetics, Vol: 12, ISSN: 1553-7390

Patterning of C. elegans vulval cell fates relies on inductive signaling. In this induction event, a single cell, the gonadal anchor cell, secretes LIN-3/EGF and induces three out of six competent precursor cells to acquire a vulval fate. We previously showed that this developmental system is robust to a four-fold variation in lin-3/EGF genetic dose. Here using single-molecule FISH, we find that the mean level of expression of lin-3 in the anchor cell is remarkably conserved. No change in lin-3 expression level could be detected among C. elegans wild isolates and only a low level of change-less than 30%-in the Caenorhabditis genus and in Oscheius tipulae. In C. elegans, lin-3 expression in the anchor cell is known to require three transcription factor binding sites, specifically two E-boxes and a nuclear-hormone-receptor (NHR) binding site. Mutation of any of these three elements in C. elegans results in a dramatic decrease in lin-3 expression. Yet only a single E-box is found in the Drosophilae supergroup of Caenorhabditis species, including C. angaria, while the NHR-binding site likely only evolved at the base of the Elegans group. We find that a transgene from C. angaria bearing a single E-box is sufficient for normal expression in C. elegans. Even a short 58 bp cis-regulatory fragment from C. angaria with this single E-box is able to replace the three transcription factor binding sites at the endogenous C. elegans lin-3 locus, resulting in the wild-type expression level. Thus, regulatory evolution occurring in cis within a 58 bp lin-3 fragment, results in a strict requirement for the NHR binding site and a second E-box in C. elegans. This single-cell, single-molecule, quantitative and functional evo-devo study demonstrates that conserved expression levels can hide extensive change in cis-regulatory site requirements and highlights the evolution of new cis-regulatory elements required for cell-specific gene expression.

Journal article

Grimbert S, Tietze K, Barkoulas M, Sternberg PW, Félix MA, Braendle Cet al., 2016, Anchor cell signaling and vulval precursor cell positioning establish a reproducible spatial context during C. elegans vulval induction, Developmental Biology, Vol: 416, Pages: 123-135, ISSN: 1095-564X

How cells coordinate their spatial positioning through intercellular signaling events is poorly understood. Here we address this topic using Caenorhabditis elegans vulval patterning during which hypodermal vulval precursor cells (VPCs) adopt distinct cell fates determined by their relative positions to the gonadal anchor cell (AC). LIN-3/EGF signaling by the AC induces the central VPC, P6.p, to adopt a 1° vulval fate. Exact alignment of AC and VPCs is thus critical for correct fate patterning, yet, as we show here, the initial AC-VPC positioning is both highly variable and asymmetric among individuals, with AC and P6.p only becoming aligned at the early L3 stage. Cell ablations and mutant analysis indicate that VPCs, most prominently 1° cells, move towards the AC. We identify AC-released LIN-3/EGF as a major attractive signal, which therefore plays a dual role in vulval patterning (cell alignment and fate induction). Additionally, compromising Wnt pathway components also induces AC-VPC alignment errors, with loss of posterior Wnt signaling increasing stochastic vulval centering on P5.p. Our results illustrate how intercellular signaling reduces initial spatial variability in cell positioning to generate reproducible interactions across tissues.

Journal article

Matus DQ, Lohmer LL, Kelley LC, Schindler AJ, Kohrman AQ, Barkoulas M, Zhang W, Chi Q, Sherwood DRet al., 2015, Invasive Cell Fate Requires G1 Cell-Cycle Arrest and Histone Deacetylase-Mediated Changes in Gene Expression, DEVELOPMENTAL CELL, Vol: 35, Pages: 162-174, ISSN: 1534-5807

Journal article

Boukhibar LM, Barkoulas M, 2015, The developmental genetics of biological robustness, Annals of Botany, Vol: 117, Pages: 699-707, ISSN: 1095-8290

Background Living organisms are continuously confronted with perturbations, such as environmental changes that include fluctuations in temperature and nutrient availability, or genetic changes such as mutations. While some developmental systems are affected by such challenges and display variation in phenotypic traits, others continue consistently to produce invariable phenotypes despite perturbation. This ability of a living system to maintain an invariable phenotype in the face of perturbations is termed developmental robustness. Biological robustness is a phenomenon observed across phyla, and studying its mechanisms is central to deciphering the genotype–phenotype relationship. Recent work in yeast, animals and plants has shown that robustness is genetically controlled and has started to reveal the underlying mechinisms behind it.Scope and Conclusions Studying biological robustness involves focusing on an important property of developmental traits, which is the phenotypic distribution within a population. This is often neglected because the vast majority of developmental biology studies instead focus on population aggregates, such as trait averages. By drawing on findings in animals and yeast, this Viewpoint considers how studies on plant developmental robustness may benefit from strict definitions of what is the developmental system of choice and what is the relevant perturbation, and also from clear distinctions between gene effects on the trait mean and the trait variance. Recent advances in quantitative developmental biology and high-throughput phenotyping now allow the design of targeted genetic screens to identify genes that amplify or restrict developmental trait variance and to study how variation propagates across different phenotypic levels in biological systems. The molecular characterization of more quantitative trait loci affecting trait variance will provide further insights into the evolution of genes modulating developmental robustness. The

Journal article

Felix M-A, Barkoulas M, 2015, Pervasive robustness in biological systems, NATURE REVIEWS GENETICS, Vol: 16, Pages: 483-496, ISSN: 1471-0056

Journal article

van Zon JS, Kienle S, Huelsz-Prince G, Barkoulas M, van Oudenaarden Aet al., 2015, Cells change their sensitivity to an EGF morphogen gradient to control EGF-induced gene expression., Nature Communications, Vol: 6, Pages: 7053-7053, ISSN: 2041-1723

How cells in developing organisms interpret the quantitative information contained in morphogen gradients is an open question. Here we address this question using a novel integrative approach that combines quantitative measurements of morphogen-induced gene expression at single-mRNA resolution with mathematical modelling of the induction process. We focus on the induction of Notch ligands by the LIN-3/EGF morphogen gradient during vulva induction in Caenorhabditis elegans. We show that LIN-3/EGF-induced Notch ligand expression is highly dynamic, exhibiting an abrupt transition from low to high expression. Similar transitions in Notch ligand expression are observed in two highly divergent wild C. elegans isolates. Mathematical modelling and experiments show that this transition is driven by a dynamic increase in the sensitivity of the induced cells to external LIN-3/EGF. Furthermore, this increase in sensitivity is independent of the presence of LIN-3/EGF. Our integrative approach might be useful to study induction by morphogen gradients in other systems.

Journal article

Hay AS, Pieper B, Cooke E, Mandakova T, Cartolano M, Tattersall AD, Ioio RD, McGowan SJ, Barkoulas M, Galinha C, Rast MI, Hofhuis H, Then C, Plieske J, Ganal M, Mott R, Martinez-Garcia JF, Carine MA, Scotland RW, Gan X, Filatov DA, Lysak MA, Tsiantis Met al., 2014, Cardamine hirsuta: a versatile genetic system for comparative studies, PLANT JOURNAL, Vol: 78, Pages: 1-15, ISSN: 0960-7412

Journal article

Barkoulas M, van Zon JS, Milloz J, van Oudenaarden A, Felix M-Aet al., 2013, Robustness and Epistasis in the C-elegans Vulval Signaling Network Revealed by Pathway Dosage Modulation, DEVELOPMENTAL CELL, Vol: 24, Pages: 64-75, ISSN: 1534-5807

Journal article

Felix M-A, Barkoulas M, 2012, Robustness and flexibility in nematode vulva development, TRENDS IN GENETICS, Vol: 28, Pages: 185-195, ISSN: 0168-9525

Journal article

Prasad K, Grigg SP, Barkoulas M, Yadav RK, Sanchez-Perez GF, Pinon V, Blilou I, Hofhuis H, Dhonukshe P, Galinha C, Mahonen AP, Muller WH, Raman S, Verkleij AJ, Snel B, Reddy GV, Tsiantis M, Scheres Bet al., 2011, Arabidopsis PLETHORA Transcription Factors Control Phyllotaxis, CURRENT BIOLOGY, Vol: 21, Pages: 1123-1128, ISSN: 0960-9822

Journal article

Hoyos E, Kim K, Milloz J, Barkoulas M, Penigault J-B, Munro E, Felix M-Aet al., 2011, Quantitative Variation in Autocrine Signaling and Pathway Crosstalk in the Caenorhabditis Vulval Network, CURRENT BIOLOGY, Vol: 21, Pages: 527-538, ISSN: 0960-9822

Journal article

Bilsborough GD, Runions A, Barkoulas M, Jenkins HW, Hasson A, Galinha C, Laufs P, Hay A, Prusinkiewicz P, Tsiantis Met al., 2011, Model for the regulation of Arabidopsis thaliana leaf margin development, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 108, Pages: 3424-3429, ISSN: 0027-8424

Journal article

Canales C, Barkoulas M, Galinha C, Tsiantis Met al., 2010, Weeds of change: Cardamine hirsuta as a new model system for studying dissected leaf development, JOURNAL OF PLANT RESEARCH, Vol: 123, Pages: 25-33, ISSN: 0918-9440

Journal article

Scarpella E, Barkoulas M, Tsiantis M, 2010, Control of Leaf and Vein Development by Auxin, COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, Vol: 2, ISSN: 1943-0264

Journal article

Jenkins H, Tattersall A, Barkoulas M, Kougioumoutzi E, Hay A, Tsiantis Met al., 2009, Dissected leaf development in Cardamine hirsuta, 16th Annual Conference of the International-Society-of-Development-Biologists, Publisher: ELSEVIER SCIENCE BV, Pages: S55-S55, ISSN: 0925-4773

Conference paper

Barkoulas M, Bilsborough G, 2009, En passant Family ties, NATURE, Vol: 458, Pages: 1212-1212, ISSN: 0028-0836

Journal article

Barkoulas M, Hay A, Kougioumoutzi E, Tsiantis Met al., 2008, A developmental framework for dissected leaf formation in the Arabidopsis relative Cardamine hirsuta, NATURE GENETICS, Vol: 40, Pages: 1136-1141, ISSN: 1061-4036

Journal article

Barkoulas M, Galinha C, Grigg SP, Tsiantis Met al., 2007, From genes to shape: regulatory interactions in leaf development, CURRENT OPINION IN PLANT BIOLOGY, Vol: 10, Pages: 660-666, ISSN: 1369-5266

Journal article

Hay A, Barkoulas M, Tsiantis M, 2006, ASYMMETRIC LEAVES1 and auxin activities converge to repress BREVIPEDICELLUS expression and promote leaf development in Arabidopsis, DEVELOPMENT, Vol: 133, Pages: 3955-3961, ISSN: 0950-1991

Journal article

Hay A, Barkoulas M, Tsiantis M, 2006, PINning down the connections: transcription factors and hormones in leaf morphogenesis (vol 9, pg 443, 2006), CURRENT OPINION IN PLANT BIOLOGY, Vol: 9, Pages: 443-443, ISSN: 1369-5266

Journal article

Hay A, Barkoulas M, Tsiantis M, 2004, PINning down the connections: transcription factors and hormones in leaf morphogenesis, CURRENT OPINION IN PLANT BIOLOGY, Vol: 7, Pages: 575-581, ISSN: 1369-5266

Journal article

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00394784&limit=30&person=true