Project acronym AAA
Project Adaptive Actin Architectures
Researcher (PI) Laurent Blanchoin
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS3, ERC-2016-ADG
Summary Although we have extensive knowledge of many important processes in cell biology, including information on many of the molecules involved and the physical interactions among them, we still do not understand most of the dynamical features that are the essence of living systems. This is particularly true for the actin cytoskeleton, a major component of the internal architecture of eukaryotic cells. In living cells, actin networks constantly assemble and disassemble filaments while maintaining an apparent stable structure, suggesting a perfect balance between the two processes. Such behaviors are called “dynamic steady states”. They confer upon actin networks a high degree of plasticity allowing them to adapt in response to external changes and enable cells to adjust to their environments. Despite their fundamental importance in the regulation of cell physiology, the basic mechanisms that control the coordinated dynamics of co-existing actin networks are poorly understood. In the AAA project, first, we will characterize the parameters that allow the coupling among co-existing actin networks at steady state. In vitro reconstituted systems will be used to control the actin nucleation patterns, the closed volume of the reaction chamber and the physical interaction of the networks. We hope to unravel the mechanism allowing the global coherence of a dynamic actin cytoskeleton. Second, we will use our unique capacity to perform dynamic micropatterning, to add or remove actin nucleation sites in real time, in order to investigate the ability of dynamic networks to adapt to changes and the role of coupled network dynamics in this emergent property. In this part, in vitro experiments will be complemented by the analysis of actin network remodeling in living cells. In the end, our project will provide a comprehensive understanding of how the adaptive response of the cytoskeleton derives from the complex interplay between its biochemical, structural and mechanical properties.
Summary
Although we have extensive knowledge of many important processes in cell biology, including information on many of the molecules involved and the physical interactions among them, we still do not understand most of the dynamical features that are the essence of living systems. This is particularly true for the actin cytoskeleton, a major component of the internal architecture of eukaryotic cells. In living cells, actin networks constantly assemble and disassemble filaments while maintaining an apparent stable structure, suggesting a perfect balance between the two processes. Such behaviors are called “dynamic steady states”. They confer upon actin networks a high degree of plasticity allowing them to adapt in response to external changes and enable cells to adjust to their environments. Despite their fundamental importance in the regulation of cell physiology, the basic mechanisms that control the coordinated dynamics of co-existing actin networks are poorly understood. In the AAA project, first, we will characterize the parameters that allow the coupling among co-existing actin networks at steady state. In vitro reconstituted systems will be used to control the actin nucleation patterns, the closed volume of the reaction chamber and the physical interaction of the networks. We hope to unravel the mechanism allowing the global coherence of a dynamic actin cytoskeleton. Second, we will use our unique capacity to perform dynamic micropatterning, to add or remove actin nucleation sites in real time, in order to investigate the ability of dynamic networks to adapt to changes and the role of coupled network dynamics in this emergent property. In this part, in vitro experiments will be complemented by the analysis of actin network remodeling in living cells. In the end, our project will provide a comprehensive understanding of how the adaptive response of the cytoskeleton derives from the complex interplay between its biochemical, structural and mechanical properties.
Max ERC Funding
2 349 898 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym APPL
Project Anionic PhosPhoLipids in plant receptor kinase signaling
Researcher (PI) Yvon Jaillais
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), LS3, ERC-2013-StG
Summary "In plants, receptor kinases form the largest family of plasma membrane (PM) receptors and they are involved in virtually all aspects of the plant life, including development, immunity and reproduction. In animals, key molecules that orchestrate the recruitment of signaling proteins to membranes are anionic phospholipids (e.g. phosphatidylinositol phosphate or PIPs). Besides, recent reports in animal and yeast cells suggest the existence of PM nanodomains that are independent of cholesterol and lipid phase and rely on anionic phospholipids as well as electrostatic protein/lipid interactions. Strikingly, we know very little on the role of anionic phospholipids in plant signaling. However, our preliminary data suggest that BKI1, an inhibitory protein of the steroid receptor kinase BRI1, interacts with various PIPs in vitro and is likely targeted to the PM by electrostatic interactions with these anionic lipids. These results open the possibility that BRI1, but also other receptor kinases, might be regulated by anionic phospholipids in plants. Here, we propose to analyze the function of anionic phospholipids in BRI1 signaling, using the root epidermis as a model system. First, we will ask what are the lipids that control membrane surface charge in this tissue and recruit BR-signaling component to the PM. Second, we will probe the presence of PIP-enriched nanodomains at the plant PM using super-resolution microscopy techniques and investigate the roles of these domains in BRI1 signaling. Finally, we will analyze the function of the BKI1-related plant-specific family of anionic phospholipid effectors in plant development. In summary, using a transversal approach ranging from in vitro studies to in vivo validation and whole organism physiology, this work will unravel the interplay between anionic phospholipids and receptor signaling in plants."
Summary
"In plants, receptor kinases form the largest family of plasma membrane (PM) receptors and they are involved in virtually all aspects of the plant life, including development, immunity and reproduction. In animals, key molecules that orchestrate the recruitment of signaling proteins to membranes are anionic phospholipids (e.g. phosphatidylinositol phosphate or PIPs). Besides, recent reports in animal and yeast cells suggest the existence of PM nanodomains that are independent of cholesterol and lipid phase and rely on anionic phospholipids as well as electrostatic protein/lipid interactions. Strikingly, we know very little on the role of anionic phospholipids in plant signaling. However, our preliminary data suggest that BKI1, an inhibitory protein of the steroid receptor kinase BRI1, interacts with various PIPs in vitro and is likely targeted to the PM by electrostatic interactions with these anionic lipids. These results open the possibility that BRI1, but also other receptor kinases, might be regulated by anionic phospholipids in plants. Here, we propose to analyze the function of anionic phospholipids in BRI1 signaling, using the root epidermis as a model system. First, we will ask what are the lipids that control membrane surface charge in this tissue and recruit BR-signaling component to the PM. Second, we will probe the presence of PIP-enriched nanodomains at the plant PM using super-resolution microscopy techniques and investigate the roles of these domains in BRI1 signaling. Finally, we will analyze the function of the BKI1-related plant-specific family of anionic phospholipid effectors in plant development. In summary, using a transversal approach ranging from in vitro studies to in vivo validation and whole organism physiology, this work will unravel the interplay between anionic phospholipids and receptor signaling in plants."
Max ERC Funding
1 797 840 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym ARFMEMBRANESENSORS
Project Membrane sensors in the Arf orbit
Researcher (PI) Bruno Antonny
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS3, ERC-2010-AdG_20100317
Summary Cellular organelles are continuously remodelled by numerous cytosolic proteins that associate transiently with their lipid membrane. Some distort the bilayer, others change its composition, extract lipids or bridge membranes at distance. Previous works from my laboratory have underlined the importance of membrane sensors, i.e. elements within proteins that help to organize membrane-remodelling events by sensing the physical and chemical state of the underlying membrane. A membrane sensor is not necessarily of well-folded domain that interacts with a specific lipid polar head: some intrinsically unfolded motifs harboring deceptively simple sequences can display remarkable membrane adhesive properties. Among these are some amphipathic helices: the ALPS motif with a polar face made mostly by small uncharged polar residues, the Spo20 helix with several histidines in its polar face and, like a mirror image of the ALPS motif, the alpha-synuclein helix with very small hydrophobic residues. Using biochemistry and molecular dynamics, we will compare the membrane binding properties of these sequences (effect of curvature, charge, lipid unsaturation); using bioinformatics we will look for new motifs, using cell biology we will assess the adaptation of these motifs to the physical and chemical features of organelle membranes. Concurrently, we will use reconstitution approaches on artificial membranes to dissect how membrane sensors contribute to the organization of vesicle tethering by golgins and sterol transport by ORP proteins. We surmise that the combination of a molecular ¿switch¿, a small G protein of the Arf family, and of membrane sensors permit to organize these complex reactions in time and in space.
Summary
Cellular organelles are continuously remodelled by numerous cytosolic proteins that associate transiently with their lipid membrane. Some distort the bilayer, others change its composition, extract lipids or bridge membranes at distance. Previous works from my laboratory have underlined the importance of membrane sensors, i.e. elements within proteins that help to organize membrane-remodelling events by sensing the physical and chemical state of the underlying membrane. A membrane sensor is not necessarily of well-folded domain that interacts with a specific lipid polar head: some intrinsically unfolded motifs harboring deceptively simple sequences can display remarkable membrane adhesive properties. Among these are some amphipathic helices: the ALPS motif with a polar face made mostly by small uncharged polar residues, the Spo20 helix with several histidines in its polar face and, like a mirror image of the ALPS motif, the alpha-synuclein helix with very small hydrophobic residues. Using biochemistry and molecular dynamics, we will compare the membrane binding properties of these sequences (effect of curvature, charge, lipid unsaturation); using bioinformatics we will look for new motifs, using cell biology we will assess the adaptation of these motifs to the physical and chemical features of organelle membranes. Concurrently, we will use reconstitution approaches on artificial membranes to dissect how membrane sensors contribute to the organization of vesicle tethering by golgins and sterol transport by ORP proteins. We surmise that the combination of a molecular ¿switch¿, a small G protein of the Arf family, and of membrane sensors permit to organize these complex reactions in time and in space.
Max ERC Funding
1 997 321 €
Duration
Start date: 2011-05-01, End date: 2015-04-30
Project acronym BACEMO
Project Bacterial Cell Morphogenesis
Researcher (PI) Rut Carballido Lopez
Host Institution (HI) INSTITUT NATIONAL DE LA RECHERCHE AGRONOMIQUE
Call Details Starting Grant (StG), LS3, ERC-2012-StG_20111109
Summary In bacteria, the though external cell wall and the intracellular actin-like (MreB) cytoskeleton are major determinants of cell shape. The biosynthetic pathways and chemical composition of the cell wall, a three dimensional polymer network that is one of the most prominent targets for antibiotics, are well understood. However, despite decades of study, little is known about the complex cell wall ultrastructure and the molecular mechanisms that control cell wall morphogenesis in time and space. In rod-shaped bacteria, MreB homologues assemble into dynamic structures thought to control shape by serving as organizers for the movement and assembly of macromolecular machineries that effect sidewall elongation. However, the mechanistic details used by the MreB cytoskeleton to fulfil this role remain to be elucidated. Furthermore, development of high-resolution microscopy techniques has led to new breakthroughs this year, published by our lab and others, which are shaking the model developed over the last decade and re-questioning the MreB “actin cytoskeleton” designation.
The aim of this project is to combine powerful genetic, biochemical, genomic and systems biology approaches available in the model bacterium Bacillus subtilis with modern high-resolution light microscopic techniques to study the dynamics and mechanistic details of the MreB cytoskeleton and of CW assembly. Parameters measured by the different approaches will be combined to quantitatively describe the features of bacterial cell morphogenesis.
Summary
In bacteria, the though external cell wall and the intracellular actin-like (MreB) cytoskeleton are major determinants of cell shape. The biosynthetic pathways and chemical composition of the cell wall, a three dimensional polymer network that is one of the most prominent targets for antibiotics, are well understood. However, despite decades of study, little is known about the complex cell wall ultrastructure and the molecular mechanisms that control cell wall morphogenesis in time and space. In rod-shaped bacteria, MreB homologues assemble into dynamic structures thought to control shape by serving as organizers for the movement and assembly of macromolecular machineries that effect sidewall elongation. However, the mechanistic details used by the MreB cytoskeleton to fulfil this role remain to be elucidated. Furthermore, development of high-resolution microscopy techniques has led to new breakthroughs this year, published by our lab and others, which are shaking the model developed over the last decade and re-questioning the MreB “actin cytoskeleton” designation.
The aim of this project is to combine powerful genetic, biochemical, genomic and systems biology approaches available in the model bacterium Bacillus subtilis with modern high-resolution light microscopic techniques to study the dynamics and mechanistic details of the MreB cytoskeleton and of CW assembly. Parameters measured by the different approaches will be combined to quantitatively describe the features of bacterial cell morphogenesis.
Max ERC Funding
1 650 050 €
Duration
Start date: 2013-02-01, End date: 2019-01-31
Project acronym BACTIN
Project Shaping the bacterial cell wall: the actin-like cytoskeleton, from single molecules to morphogenesis and antimicrobials
Researcher (PI) Rut CARBALLIDO LOPEZ
Host Institution (HI) INSTITUT NATIONAL DE LA RECHERCHE AGRONOMIQUE
Call Details Consolidator Grant (CoG), LS3, ERC-2017-COG
Summary One of the ultimate goals in cell biology is to understand how cells determine their shape. In bacteria, the cell wall and the actin-like (MreB) cytoskeleton are major determinants of cell shape. As a hallmark of microbial life, the external cell wall is the most conspicuous macromolecule expanding in concert with cell growth and one of the most prominent targets for antibiotics. Despite decades of study, the mechanism of cell wall morphogenesis remains poorly understood. In rod-shaped bacteria, actin-like MreB proteins assemble into disconnected membrane-associated structures (patches) that move processively around the cell periphery and are thought to control shape by spatiotemporally organizing macromolecular machineries that effect sidewall elongation. However, the ultrastructure of MreB assemblies and the mechanistic details underlying their morphogenetic function remain to be elucidated.
The aim of this project is to combine ground-breaking light microscopy and spectroscopy techniques with cutting-edge genetic, biochemical and systems biology approaches available in the model rod-shaped bacterium Bacillus subtilis to elucidate how MreB and cell wall biosynthetic enzymes collectively act to build a cell. Within this context, new features of MreB assemblies will be determined in vivo and in vitro, and a “toolbox” of approaches to determine the modes of action of antibiotics targeting cell wall processes will be developed. Parameters measured by the different approaches will be used to refine a mathematical model aiming to quantitatively describe the features of bacterial cell wall growth. The long-term goals of BActin are to understand general principles of bacterial cell morphogenesis and to provide mechanistic templates and new reporters for the screening of novel antibiotics.
Summary
One of the ultimate goals in cell biology is to understand how cells determine their shape. In bacteria, the cell wall and the actin-like (MreB) cytoskeleton are major determinants of cell shape. As a hallmark of microbial life, the external cell wall is the most conspicuous macromolecule expanding in concert with cell growth and one of the most prominent targets for antibiotics. Despite decades of study, the mechanism of cell wall morphogenesis remains poorly understood. In rod-shaped bacteria, actin-like MreB proteins assemble into disconnected membrane-associated structures (patches) that move processively around the cell periphery and are thought to control shape by spatiotemporally organizing macromolecular machineries that effect sidewall elongation. However, the ultrastructure of MreB assemblies and the mechanistic details underlying their morphogenetic function remain to be elucidated.
The aim of this project is to combine ground-breaking light microscopy and spectroscopy techniques with cutting-edge genetic, biochemical and systems biology approaches available in the model rod-shaped bacterium Bacillus subtilis to elucidate how MreB and cell wall biosynthetic enzymes collectively act to build a cell. Within this context, new features of MreB assemblies will be determined in vivo and in vitro, and a “toolbox” of approaches to determine the modes of action of antibiotics targeting cell wall processes will be developed. Parameters measured by the different approaches will be used to refine a mathematical model aiming to quantitatively describe the features of bacterial cell wall growth. The long-term goals of BActin are to understand general principles of bacterial cell morphogenesis and to provide mechanistic templates and new reporters for the screening of novel antibiotics.
Max ERC Funding
1 902 195 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym BCLYM
Project Molecular mechanisms of mature B cell lymphomagenesis
Researcher (PI) Almudena Ramiro
Host Institution (HI) CENTRO NACIONAL DE INVESTIGACIONESCARDIOVASCULARES CARLOS III (F.S.P.)
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary Most of the lymphomas diagnosed in the western world are originated from mature B cells. The hallmark of these malignancies is the presence of recurrent chromosome translocations that usually involve the immunoglobulin loci and a proto-oncogene. As a result of the translocation event the proto-oncogene becomes deregulated under the influence of immunoglobulin cis sequences thus playing an important role in the etiology of the disease. Upon antigen encounter mature B cells engage in the germinal center reaction, a complex differentiation program of critical importance to the development of the secondary immune response. The germinal center reaction entails the somatic remodelling of immunoglobulin genes by the somatic hypermutation and class switch recombination reactions, both of which are triggered by Activation Induced Deaminase (AID). We have previously shown that AID also initiates lymphoma-associated c-myc/IgH chromosome translocations. In addition, the germinal center reaction involves a fine-tuned balance between intense B cell proliferation and program cell death. This environment seems to render B cells particularly vulnerable to malignant transformation. We aim at studying the molecular events responsible for B cell susceptibility to lymphomagenesis from two perspectives. First, we will address the role of AID in the generation of lymphomagenic lesions in the context of AID specificity and transcriptional activation. Second, we will approach the regulatory function of microRNAs of AID-dependent, germinal center events. The proposal aims at the molecular understanding of a process that lies in the interface of immune regulation and oncogenic transformation and therefore the results will have profound implications both to basic and clinical understanding of lymphomagenesis.
Summary
Most of the lymphomas diagnosed in the western world are originated from mature B cells. The hallmark of these malignancies is the presence of recurrent chromosome translocations that usually involve the immunoglobulin loci and a proto-oncogene. As a result of the translocation event the proto-oncogene becomes deregulated under the influence of immunoglobulin cis sequences thus playing an important role in the etiology of the disease. Upon antigen encounter mature B cells engage in the germinal center reaction, a complex differentiation program of critical importance to the development of the secondary immune response. The germinal center reaction entails the somatic remodelling of immunoglobulin genes by the somatic hypermutation and class switch recombination reactions, both of which are triggered by Activation Induced Deaminase (AID). We have previously shown that AID also initiates lymphoma-associated c-myc/IgH chromosome translocations. In addition, the germinal center reaction involves a fine-tuned balance between intense B cell proliferation and program cell death. This environment seems to render B cells particularly vulnerable to malignant transformation. We aim at studying the molecular events responsible for B cell susceptibility to lymphomagenesis from two perspectives. First, we will address the role of AID in the generation of lymphomagenic lesions in the context of AID specificity and transcriptional activation. Second, we will approach the regulatory function of microRNAs of AID-dependent, germinal center events. The proposal aims at the molecular understanding of a process that lies in the interface of immune regulation and oncogenic transformation and therefore the results will have profound implications both to basic and clinical understanding of lymphomagenesis.
Max ERC Funding
1 596 000 €
Duration
Start date: 2008-12-01, End date: 2014-11-30
Project acronym BinD
Project Mitotic Bookmarking, Stem Cells and early Development
Researcher (PI) Pablo Navarro Gil
Host Institution (HI) INSTITUT PASTEUR
Call Details Consolidator Grant (CoG), LS3, ERC-2017-COG
Summary The goal of this proposal is to deliver a new theoretical framework to understand how transcription factors (TFs) sustain cell identity during developmental processes. Recognised as key drivers of cell fate acquisition, TFs are currently not considered to directly contribute to the mitotic inheritance of chromatin states. Instead, these are passively propagated through cell division by a variety of epigenetic marks. Recent discoveries, including by our lab, challenge this view: developmental TFs may impact the propagation of regulatory information from mother to daughter cells through a process known as mitotic bookmarking. This hypothesis, largely overlooked by mainstream epigenetic research during the last two decades, will be investigated in embryo-derived stem cells and during early mouse development. Indeed, these immature cell identities are largely independent from canonical epigenetic repression; hence, current models cannot account for their properties. We will comprehensively identify mitotic bookmarking factors in stem cells and early embryos, establish their function in stem cell self-renewal, cell fate acquisition and dissect how they contribute to chromatin regulation in mitosis. This will allow us to study the relationships between bookmarking factors and other mechanisms of epigenetic inheritance. To achieve this, unique techniques to modulate protein activity and histone modifications specifically in mitotic cells will be established. Thus, a mechanistic understanding of how mitosis influences gene regulation and of how mitotic bookmarking contributes to the propagation of immature cell identities will be delivered. Based on robust preliminary data, we anticipate the discovery of new functions for TFs in several genetic and epigenetic processes. This knowledge should have a wide impact on chromatin biology and cell fate studies as well as in other fields studying processes dominated by TFs and cell proliferation.
Summary
The goal of this proposal is to deliver a new theoretical framework to understand how transcription factors (TFs) sustain cell identity during developmental processes. Recognised as key drivers of cell fate acquisition, TFs are currently not considered to directly contribute to the mitotic inheritance of chromatin states. Instead, these are passively propagated through cell division by a variety of epigenetic marks. Recent discoveries, including by our lab, challenge this view: developmental TFs may impact the propagation of regulatory information from mother to daughter cells through a process known as mitotic bookmarking. This hypothesis, largely overlooked by mainstream epigenetic research during the last two decades, will be investigated in embryo-derived stem cells and during early mouse development. Indeed, these immature cell identities are largely independent from canonical epigenetic repression; hence, current models cannot account for their properties. We will comprehensively identify mitotic bookmarking factors in stem cells and early embryos, establish their function in stem cell self-renewal, cell fate acquisition and dissect how they contribute to chromatin regulation in mitosis. This will allow us to study the relationships between bookmarking factors and other mechanisms of epigenetic inheritance. To achieve this, unique techniques to modulate protein activity and histone modifications specifically in mitotic cells will be established. Thus, a mechanistic understanding of how mitosis influences gene regulation and of how mitotic bookmarking contributes to the propagation of immature cell identities will be delivered. Based on robust preliminary data, we anticipate the discovery of new functions for TFs in several genetic and epigenetic processes. This knowledge should have a wide impact on chromatin biology and cell fate studies as well as in other fields studying processes dominated by TFs and cell proliferation.
Max ERC Funding
1 900 844 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym BIOMECAMORPH
Project The Biomechanics of Epithelial Cell and Tissue Morphogenesis
Researcher (PI) Thomas Marie Michel Lecuit
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS3, ERC-2012-ADG_20120314
Summary Tissue morphogenesis is a complex process that emerges from spatially controlled patterns of cell shape changes. Dedicated genetic programmes regulate cell behaviours, exemplified in animals by the specification of apical constriction in invaginating epithelial tissues, or the orientation of cell intercalation during tissue extension. This genetic control is constrained by physical properties of cells that dictate how they can modify their shape. A major challenge is to understand how biochemical pathways control subcellular mechanics in epithelia, such as how forces are produced by interactions between actin filaments and myosin motors, and how these forces are transmitted at cell junctions. The major objective of our project is to investigate the fundamental principles of epithelial mechanics and to understand how intercellular signals and mechanical coupling between cells coordinate individual behaviours at the tissue level.
We will study early Drosophila embryogenesis and combine quantitative cell biological studies of cell dynamics, biophysical characterization of cell mechanics and genetic control of cell signalling to answer the following questions: i) how are forces generated, in particular what underlies deformation and stabilization of cell shape by actomyosin networks, and pulsatile contractility; ii) how are forces transmitted at junctions, what are the feedback interactions between tension generation and transmission; iii) how are individual cell mechanics orchestrated at the tissue level to yield collective tissue morphogenesis?
We expect to encapsulate the information-based, cell biological and physical descriptions of morphogenesis in a single, coherent framework. The project should impact more broadly on morphogenesis in other organisms and shed light on the mechanisms underlying robustness and plasticity in epithelia.
Summary
Tissue morphogenesis is a complex process that emerges from spatially controlled patterns of cell shape changes. Dedicated genetic programmes regulate cell behaviours, exemplified in animals by the specification of apical constriction in invaginating epithelial tissues, or the orientation of cell intercalation during tissue extension. This genetic control is constrained by physical properties of cells that dictate how they can modify their shape. A major challenge is to understand how biochemical pathways control subcellular mechanics in epithelia, such as how forces are produced by interactions between actin filaments and myosin motors, and how these forces are transmitted at cell junctions. The major objective of our project is to investigate the fundamental principles of epithelial mechanics and to understand how intercellular signals and mechanical coupling between cells coordinate individual behaviours at the tissue level.
We will study early Drosophila embryogenesis and combine quantitative cell biological studies of cell dynamics, biophysical characterization of cell mechanics and genetic control of cell signalling to answer the following questions: i) how are forces generated, in particular what underlies deformation and stabilization of cell shape by actomyosin networks, and pulsatile contractility; ii) how are forces transmitted at junctions, what are the feedback interactions between tension generation and transmission; iii) how are individual cell mechanics orchestrated at the tissue level to yield collective tissue morphogenesis?
We expect to encapsulate the information-based, cell biological and physical descriptions of morphogenesis in a single, coherent framework. The project should impact more broadly on morphogenesis in other organisms and shed light on the mechanisms underlying robustness and plasticity in epithelia.
Max ERC Funding
2 473 313 €
Duration
Start date: 2013-05-01, End date: 2018-04-30
Project acronym BODYBUILT
Project Building The Vertebrate Body
Researcher (PI) Olivier Pourquie
Host Institution (HI) CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET MEDECINE
Call Details Advanced Grant (AdG), LS3, ERC-2009-AdG
Summary My lab is interested in the development of the tissue that gives rise to vertebrae and skeletal muscles called the paraxial mesoderm. A striking feature of this tissue is its segmental organization and we have made major contributions to the understanding of the molecular control of the segmentation process. We identified a molecular oscillator associated to the rhythmic production of somites and proposed a model for vertebrate segmentation based on the integration of a rhythmic signaling pulse gated spatially by a system of traveling FGF and Wnt signaling gradients. We are also studying the differentiation of paraxial mesoderm precursors into the muscle, cartilage and dermis lineages. Our work identified the Wnt, FGF and Notch pathways as playing a prominent role in the patterning and differentiation of paraxial mesoderm. In this application, we largely focus on the molecular control of paraxial mesoderm development. Using microarray and high throughput sequencing-based approaches and bioinformatics, we will characterize the transcriptional network acting downstream of Wnt, FGF and Notch in the presomitic mesoderm (PSM). We will also use genetic and pharmacological approaches utilizing real-time imaging reporters to characterize the pacemaker of the segmentation clock in vivo, and also in vitro using differentiated embryonic stem cells. We further propose to characterize in detail a novel RA-dependent pathway that we identified and which controls the somite left-right symmetry. Our work is expected to have a strong impact in the field of congenital spine anomalies, currently an understudied biomedical problem, and will be of utility in elucidating the etiology and eventual prevention of these disorders. This work is also expected to further our understanding of the Notch, Wnt, FGF and RA signalling pathways which are involved in segmentation and in the establishment of the vertebrate body plan, and which play important roles in a wide array of human diseases.
Summary
My lab is interested in the development of the tissue that gives rise to vertebrae and skeletal muscles called the paraxial mesoderm. A striking feature of this tissue is its segmental organization and we have made major contributions to the understanding of the molecular control of the segmentation process. We identified a molecular oscillator associated to the rhythmic production of somites and proposed a model for vertebrate segmentation based on the integration of a rhythmic signaling pulse gated spatially by a system of traveling FGF and Wnt signaling gradients. We are also studying the differentiation of paraxial mesoderm precursors into the muscle, cartilage and dermis lineages. Our work identified the Wnt, FGF and Notch pathways as playing a prominent role in the patterning and differentiation of paraxial mesoderm. In this application, we largely focus on the molecular control of paraxial mesoderm development. Using microarray and high throughput sequencing-based approaches and bioinformatics, we will characterize the transcriptional network acting downstream of Wnt, FGF and Notch in the presomitic mesoderm (PSM). We will also use genetic and pharmacological approaches utilizing real-time imaging reporters to characterize the pacemaker of the segmentation clock in vivo, and also in vitro using differentiated embryonic stem cells. We further propose to characterize in detail a novel RA-dependent pathway that we identified and which controls the somite left-right symmetry. Our work is expected to have a strong impact in the field of congenital spine anomalies, currently an understudied biomedical problem, and will be of utility in elucidating the etiology and eventual prevention of these disorders. This work is also expected to further our understanding of the Notch, Wnt, FGF and RA signalling pathways which are involved in segmentation and in the establishment of the vertebrate body plan, and which play important roles in a wide array of human diseases.
Max ERC Funding
2 500 000 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym BRIDGING
Project The function of membrane tethering in plant intercellular communication
Researcher (PI) Emmanuelle Maria Françoise Bayer
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Consolidator Grant (CoG), LS3, ERC-2017-COG
Summary Intercellular communication is critical for multicellularity. It coordinates the activities within individual cells to support the function of an organism as a whole. Plants have developed remarkable cellular machines -the Plasmodesmata (PD) pores- which interconnect every single cell within the plant body, establishing direct membrane and cytoplasmic continuity, a situation unique to plants. PD are indispensable for plant life. They control the flux of molecules between cells and are decisive for development, environmental adaptation and defence signalling. However, how PD integrate signalling to coordinate responses at a multicellular level remains unclear.
A striking feature of PD organisation, setting them apart from animal cell junctions, is a strand of endoplasmic reticulum (ER) running through the pore, tethered extremely tight (~10nm) to the plasma membrane (PM) by unidentified “spokes”. To date, the function of ER-PM contacts at PD remains a complete enigma. We don’t know how and why the two organelles come together at PD cellular junctions.
I recently proposed that ER-PM tethering is in fact central to PD function. In this project I will investigate the question of how integrated cellular responses benefit from organelle cross-talk at PD. The project integrates proteomic/bioinformatic approaches, biophysical/modelling methods and ultra-high resolution 3D imaging into molecular cell biology of plant cell-to-cell communication and will, for the first time, directly address the mechanism and function of ER-PM contacts at PD. We will pursue three complementary objectives to attain our goal: 1) Identify the mechanisms of PD membrane-tethering at the molecular level 2) Elucidate the dynamics and 3D architecture of ER-PM contact sites at PD 3) Uncover the function of ER-PM apposition for plant intercellular communication. Overall, the project will pioneer a radically new perspective on PD-mediated cell-to-cell communication, a fundamental aspect of plant biology
Summary
Intercellular communication is critical for multicellularity. It coordinates the activities within individual cells to support the function of an organism as a whole. Plants have developed remarkable cellular machines -the Plasmodesmata (PD) pores- which interconnect every single cell within the plant body, establishing direct membrane and cytoplasmic continuity, a situation unique to plants. PD are indispensable for plant life. They control the flux of molecules between cells and are decisive for development, environmental adaptation and defence signalling. However, how PD integrate signalling to coordinate responses at a multicellular level remains unclear.
A striking feature of PD organisation, setting them apart from animal cell junctions, is a strand of endoplasmic reticulum (ER) running through the pore, tethered extremely tight (~10nm) to the plasma membrane (PM) by unidentified “spokes”. To date, the function of ER-PM contacts at PD remains a complete enigma. We don’t know how and why the two organelles come together at PD cellular junctions.
I recently proposed that ER-PM tethering is in fact central to PD function. In this project I will investigate the question of how integrated cellular responses benefit from organelle cross-talk at PD. The project integrates proteomic/bioinformatic approaches, biophysical/modelling methods and ultra-high resolution 3D imaging into molecular cell biology of plant cell-to-cell communication and will, for the first time, directly address the mechanism and function of ER-PM contacts at PD. We will pursue three complementary objectives to attain our goal: 1) Identify the mechanisms of PD membrane-tethering at the molecular level 2) Elucidate the dynamics and 3D architecture of ER-PM contact sites at PD 3) Uncover the function of ER-PM apposition for plant intercellular communication. Overall, the project will pioneer a radically new perspective on PD-mediated cell-to-cell communication, a fundamental aspect of plant biology
Max ERC Funding
1 999 840 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
