Project acronym ASYMMEM
Project Lipid asymmetry: a cellular battery?
Researcher (PI) André NADLER
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), LS3, ERC-2017-STG
Summary It is a basic textbook notion that the plasma membranes of virtually all organisms display an asymmetric lipid distribution between inner and outer leaflets far removed from thermodynamic equilibrium. As a fundamental biological principle, lipid asymmetry has been linked to numerous cellular processes. However, a clear mechanistic justification for the continued existence of lipid asymmetry throughout evolution has yet to be established. We propose here that lipid asymmetry serves as a store of potential energy that is used to fuel energy-intense membrane remodelling and signalling events for instance during membrane fusion and fission. This implies that rapid, local changes of trans-membrane lipid distribution rather than a continuously maintained out-of-equilibrium situation are crucial for cellular function. Consequently, new methods for quantifying the kinetics of lipid trans-bilayer movement are required, as traditional approaches are mostly suited for analysing quasi-steady-state conditions. Addressing this need, we will develop and employ novel photochemical lipid probes and lipid biosensors to quantify localized trans-bilayer lipid movement. We will use these tools for identifying yet unknown protein components of the lipid asymmetry regulating machinery and analyse their function with regard to membrane dynamics and signalling in cell motility. Focussing on cell motility enables targeted chemical and genetic perturbations while monitoring lipid dynamics on timescales and in membrane structures that are well suited for light microscopy. Ultimately, we aim to reconstitute lipid asymmetry as a driving force for membrane remodelling in vitro. We expect that our work will break new ground in explaining one of the least understood features of the plasma membrane and pave the way for a new, dynamic membrane model. Since the plasma membrane serves as the major signalling hub, this will have impact in almost every area of the life sciences.
Summary
It is a basic textbook notion that the plasma membranes of virtually all organisms display an asymmetric lipid distribution between inner and outer leaflets far removed from thermodynamic equilibrium. As a fundamental biological principle, lipid asymmetry has been linked to numerous cellular processes. However, a clear mechanistic justification for the continued existence of lipid asymmetry throughout evolution has yet to be established. We propose here that lipid asymmetry serves as a store of potential energy that is used to fuel energy-intense membrane remodelling and signalling events for instance during membrane fusion and fission. This implies that rapid, local changes of trans-membrane lipid distribution rather than a continuously maintained out-of-equilibrium situation are crucial for cellular function. Consequently, new methods for quantifying the kinetics of lipid trans-bilayer movement are required, as traditional approaches are mostly suited for analysing quasi-steady-state conditions. Addressing this need, we will develop and employ novel photochemical lipid probes and lipid biosensors to quantify localized trans-bilayer lipid movement. We will use these tools for identifying yet unknown protein components of the lipid asymmetry regulating machinery and analyse their function with regard to membrane dynamics and signalling in cell motility. Focussing on cell motility enables targeted chemical and genetic perturbations while monitoring lipid dynamics on timescales and in membrane structures that are well suited for light microscopy. Ultimately, we aim to reconstitute lipid asymmetry as a driving force for membrane remodelling in vitro. We expect that our work will break new ground in explaining one of the least understood features of the plasma membrane and pave the way for a new, dynamic membrane model. Since the plasma membrane serves as the major signalling hub, this will have impact in almost every area of the life sciences.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
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 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 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
Project acronym CoSpaDD
Project Competition for Space in Development and Diseases
Researcher (PI) Romain LEVAYER
Host Institution (HI) INSTITUT PASTEUR
Call Details Starting Grant (StG), LS3, ERC-2017-STG
Summary Developing tissues have a remarkable plasticity illustrated by their capacity to regenerate and form normal organs despite strong perturbations. This requires the adjustment of single cell behaviour to their neighbours and to tissue scale parameters. The modulation of cell growth and proliferation was suggested to be driven by mechanical inputs, however the mechanisms adjusting cell death are not well known. Recently it was shown that epithelial cells could be eliminated by spontaneous live-cell delamination following an increase of cell density. Studying cell delamination in the midline region of the Drosophila pupal notum, we confirmed that local tissue crowding is necessary and sufficient to drive cell elimination and found that Caspase 3 activation precedes and is required for cell delamination. This suggested that a yet unknown pathway is responsible for crowding sensing and activation of caspase, which does not involve already known mechanical sensing pathways. Moreover, we showed that fast growing clones in the notum could induce neighbouring cell elimination through crowding-induced death. This suggested that crowding-induced death could promote tissue invasion by pretumoural cells.
Here we will combine genetics, quantitative live imaging, statistics, laser perturbations and modelling to study crowding-induced death in Drosophila in order to: 1) find single cell deformations responsible for caspase activation; 2) find new pathways responsible for density sensing and apoptosis induction; 3) test their contribution to adult tissue homeostasis, morphogenesis and cell elimination coordination; 4) study the role of crowding induced death during competition between different cell types and tissue invasion 5) Explore theoretically the conditions required for efficient space competition between two cell populations.
This project will provide essential information for the understanding of epithelial homeostasis, mechanotransduction and tissue invasion by tumoural cells
Summary
Developing tissues have a remarkable plasticity illustrated by their capacity to regenerate and form normal organs despite strong perturbations. This requires the adjustment of single cell behaviour to their neighbours and to tissue scale parameters. The modulation of cell growth and proliferation was suggested to be driven by mechanical inputs, however the mechanisms adjusting cell death are not well known. Recently it was shown that epithelial cells could be eliminated by spontaneous live-cell delamination following an increase of cell density. Studying cell delamination in the midline region of the Drosophila pupal notum, we confirmed that local tissue crowding is necessary and sufficient to drive cell elimination and found that Caspase 3 activation precedes and is required for cell delamination. This suggested that a yet unknown pathway is responsible for crowding sensing and activation of caspase, which does not involve already known mechanical sensing pathways. Moreover, we showed that fast growing clones in the notum could induce neighbouring cell elimination through crowding-induced death. This suggested that crowding-induced death could promote tissue invasion by pretumoural cells.
Here we will combine genetics, quantitative live imaging, statistics, laser perturbations and modelling to study crowding-induced death in Drosophila in order to: 1) find single cell deformations responsible for caspase activation; 2) find new pathways responsible for density sensing and apoptosis induction; 3) test their contribution to adult tissue homeostasis, morphogenesis and cell elimination coordination; 4) study the role of crowding induced death during competition between different cell types and tissue invasion 5) Explore theoretically the conditions required for efficient space competition between two cell populations.
This project will provide essential information for the understanding of epithelial homeostasis, mechanotransduction and tissue invasion by tumoural cells
Max ERC Funding
1 489 147 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym EvoCellBio
Project A combined in vitro and in vivo approach to dissect biochemical network evolution.
Researcher (PI) Liedewij LAAN
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Call Details Starting Grant (StG), LS3, ERC-2017-STG
Summary How do organisms evolve? I propose to study how biochemical networks reorganize during evolution without compromising fitness. This is a complex problem: firstly, it is hard to know if a mutation increased fitness because this depends on the environment it arose in, which is typically unknown. Secondly, it is hard to find out how adaptive mutations improve fitness, because in cells, all biochemical networks are connected. I will reduce the complexity by two approaches, focused on symmetry-breaking in budding yeast, a functionally conserved process, which is the first step for polarity establishment and essential for proliferation.
First, I will study how adaptive mutations improve fitness in yeast cells, which are evolved after the deletion of an important symmetry-breaking gene. I will use fluorescent live-cell microscopy of polarisation markers to measure fitness, defined as the rate of symmetry breaking. I will combine my data with a kinetic mathematical model to determine how specific network structures facilitate evolutionary network reorganisation.
Second, to test predicted network structures, I will build minimal evolvable networks for symmetry breaking in vitro. In my definition of such a network, all of the components are essential for either fitness or evolvability. I will encapsulate the necessary proteins in emulsion droplets to form a functional evolvable network and use fluorescence microscopy to measure its fitness (the rate of a single protein-spot formation on a droplet membrane) and evolvability (the number of accessible neutral or adaptive mutations in the one-step mutational landscape of the network). Next, I will study how increasing the number of components affects the network’s evolvability and fitness.
This research will explain how proteins essential in one species have been lost in closely related species. My expertise with in vitro systems, modelling, biophysics and evolution makes me uniquely qualified for this ambitious project.
Summary
How do organisms evolve? I propose to study how biochemical networks reorganize during evolution without compromising fitness. This is a complex problem: firstly, it is hard to know if a mutation increased fitness because this depends on the environment it arose in, which is typically unknown. Secondly, it is hard to find out how adaptive mutations improve fitness, because in cells, all biochemical networks are connected. I will reduce the complexity by two approaches, focused on symmetry-breaking in budding yeast, a functionally conserved process, which is the first step for polarity establishment and essential for proliferation.
First, I will study how adaptive mutations improve fitness in yeast cells, which are evolved after the deletion of an important symmetry-breaking gene. I will use fluorescent live-cell microscopy of polarisation markers to measure fitness, defined as the rate of symmetry breaking. I will combine my data with a kinetic mathematical model to determine how specific network structures facilitate evolutionary network reorganisation.
Second, to test predicted network structures, I will build minimal evolvable networks for symmetry breaking in vitro. In my definition of such a network, all of the components are essential for either fitness or evolvability. I will encapsulate the necessary proteins in emulsion droplets to form a functional evolvable network and use fluorescence microscopy to measure its fitness (the rate of a single protein-spot formation on a droplet membrane) and evolvability (the number of accessible neutral or adaptive mutations in the one-step mutational landscape of the network). Next, I will study how increasing the number of components affects the network’s evolvability and fitness.
This research will explain how proteins essential in one species have been lost in closely related species. My expertise with in vitro systems, modelling, biophysics and evolution makes me uniquely qualified for this ambitious project.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym EvolvingEconomics
Project Human motivation: evolutionary foundations and their implications for economics
Researcher (PI) Karin Ingela Maria ALGER
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), SH1, ERC-2017-ADG
Summary Economics provides decision-makers with powerful tools to analyse a wide range of issues. The methodological unity of the discipline and its quest for a general understanding of market as well as non-market interactions have given the discipline great influence on policy. A core component of economics is its assumption that individuals act as if they each had some goal function that they seek to maximise, under the constraints they face and the information they have.
Despite significant advances in behavioural economics, there still is no consensus as to whether and why certain preferences are more likely than others. Further progress could be made if the factors that shape human motivation in the first place were understood. The aim of this project is to produce novel insights about such factors, by establishing evolutionary foundations of human motivation.The project's scope is ambitious. First, it will study two large classes of interactions: strategic interactions, and interactions within the realm of the family. Second, to obtain both depth and breadth of insights, it will consist of four different, but inter-related, components (three theoretical and one empirical), the ultimate goal being to significantly enhance our overall understanding of the factors that shape human motivation.
The methodology is ground-breaking in that it is strongly interdisciplinary. Parts of the body of knowledge built by biologists and evolutionary anthropologists in the past decades will be combined with state-of-the-art economics to produce insights that cannot be obtained within any single discipline. Focus will nonetheless be on addressing issues of importance for economists.The proposed research builds on extensive work done by the PI in the past decade. It will benefit from the years that the PI has invested in understanding the biology and the evolutionary anthropology literatures, and in contributing towards building an interdisciplinary research ecosystem in Toulouse, France
Summary
Economics provides decision-makers with powerful tools to analyse a wide range of issues. The methodological unity of the discipline and its quest for a general understanding of market as well as non-market interactions have given the discipline great influence on policy. A core component of economics is its assumption that individuals act as if they each had some goal function that they seek to maximise, under the constraints they face and the information they have.
Despite significant advances in behavioural economics, there still is no consensus as to whether and why certain preferences are more likely than others. Further progress could be made if the factors that shape human motivation in the first place were understood. The aim of this project is to produce novel insights about such factors, by establishing evolutionary foundations of human motivation.The project's scope is ambitious. First, it will study two large classes of interactions: strategic interactions, and interactions within the realm of the family. Second, to obtain both depth and breadth of insights, it will consist of four different, but inter-related, components (three theoretical and one empirical), the ultimate goal being to significantly enhance our overall understanding of the factors that shape human motivation.
The methodology is ground-breaking in that it is strongly interdisciplinary. Parts of the body of knowledge built by biologists and evolutionary anthropologists in the past decades will be combined with state-of-the-art economics to produce insights that cannot be obtained within any single discipline. Focus will nonetheless be on addressing issues of importance for economists.The proposed research builds on extensive work done by the PI in the past decade. It will benefit from the years that the PI has invested in understanding the biology and the evolutionary anthropology literatures, and in contributing towards building an interdisciplinary research ecosystem in Toulouse, France
Max ERC Funding
1 550 891 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym HITSCIL
Project How intraflagellar transport shapes the cilium: a single-molecule systems study
Researcher (PI) Erwin J G PETERMAN
Host Institution (HI) STICHTING VU
Call Details Advanced Grant (AdG), LS3, ERC-2017-ADG
Summary Sensory cilia are organelles extending like antennas from many eukaryotic cells, with crucial functions in sensing and signalling. Cilia consist of an axoneme built of microtubules, enveloped by a specialized membrane. Ciliary development and maintenance depend critically on a specific, microtubule-based intracellular transport mechanism, intraflagellar transport (IFT). In my laboratory, we study the chemosensory cilia of C. elegans, which sense water-soluble molecules in the animal’s environment for chemotaxis. Over the past years, we have developed a unique set of quantitative, single-molecule fluorescence microscopy tools that allow us to visualize and quantify IFT dynamics with unprecedented detail in living animals. So far, our focus has been on the cooperation of the motor proteins driving IFT. The overall objective of my current proposal is to zoom out and shed light on the connection between ciliary structure, chemosensory function and IFT, from a systems perspective. Recent work has indicated that axoneme length is controlled by IFT. Preliminary results from my laboratory show that axoneme length changes dynamically in response to perturbations of IFT or cilia. Furthermore, we have shown that IFT is substantially affected upon exposure of animals to known repellent solutions. The four major aims in my proposal are to:
• determine how directional changes in IFT are regulated and are affected by external disturbances,
• understand the dynamics of the axonemal microtubules and how IFT affects these dynamics and vice versa,
• study how sensory ciliary function affects IFT and ciliary structure,
• further develop our (single-molecule) fluorescence microscopy toolbox by improving instrumentation and using better fluorescent probes and sensors.
These experiments will place my lab in a unique position to push forward our understanding of the relationship between structure, function and dynamics of transport of this fascinating and fundamental organelle.
Summary
Sensory cilia are organelles extending like antennas from many eukaryotic cells, with crucial functions in sensing and signalling. Cilia consist of an axoneme built of microtubules, enveloped by a specialized membrane. Ciliary development and maintenance depend critically on a specific, microtubule-based intracellular transport mechanism, intraflagellar transport (IFT). In my laboratory, we study the chemosensory cilia of C. elegans, which sense water-soluble molecules in the animal’s environment for chemotaxis. Over the past years, we have developed a unique set of quantitative, single-molecule fluorescence microscopy tools that allow us to visualize and quantify IFT dynamics with unprecedented detail in living animals. So far, our focus has been on the cooperation of the motor proteins driving IFT. The overall objective of my current proposal is to zoom out and shed light on the connection between ciliary structure, chemosensory function and IFT, from a systems perspective. Recent work has indicated that axoneme length is controlled by IFT. Preliminary results from my laboratory show that axoneme length changes dynamically in response to perturbations of IFT or cilia. Furthermore, we have shown that IFT is substantially affected upon exposure of animals to known repellent solutions. The four major aims in my proposal are to:
• determine how directional changes in IFT are regulated and are affected by external disturbances,
• understand the dynamics of the axonemal microtubules and how IFT affects these dynamics and vice versa,
• study how sensory ciliary function affects IFT and ciliary structure,
• further develop our (single-molecule) fluorescence microscopy toolbox by improving instrumentation and using better fluorescent probes and sensors.
These experiments will place my lab in a unique position to push forward our understanding of the relationship between structure, function and dynamics of transport of this fascinating and fundamental organelle.
Max ERC Funding
2 499 580 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym ICEBERG
Project Exploration below the tip of the microtubule
Researcher (PI) Manuel THERY
Host Institution (HI) COMMISSARIAT A L ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES
Call Details Consolidator Grant (CoG), LS3, ERC-2017-COG
Summary Microtubules (MTs) are dynamic cytoskeleton filaments. They permanently transit between growth and shrinkage. This famous “dynamic instability” is governed by the addition and loss of tubulin dimers at their tips. In contrast to the tip, the MT lattice was considered to be a passive structure supporting intracellular transport. However, we recently found that MT lattice is dynamic and active! Actually, tubulin dimers can be exchanged with the cytoplasmic pool along the entire length of the MT. These incorporations can repair sites on the lattice that have been mechanically damaged. These repair sites protect the MTs from depolymerisation and increase the MT’s life span. This discovery opens up a new vista for understanding MT biology.
First, we will investigate the biochemical consequences of MT-lattice turnover. We hypothesise that tubulin turnover affects the recruitment of MAPs, motors and tubulin-modifying enzymes. These recruitments may feedback on lattice turnover and further regulate MT life span and functions.
Second, we will investigate the mechanical impact of the MT-lattice plasticity. Tubulin removal is likely to be associated with a local reduction of MT stiffness that can impact MT shape and the propagation of forces along the lattice. We anticipate that such effects will require us to reformulate the biophysical rules directing network architecture.
To achieve this, we will use reconstituted MT networks in vitro to investigate the molecular mechanism regulating MT-lattice plasticity, and cultured cells to test the physiological relevance of these mechanisms. In both approaches, microfabricated devices will be used to control the spatial boundary conditions directing MT self-organisation.
By exploring the hidden 90% of MT iceberg we aim to show that the MT lattice is a dynamic mechano-sensory structure which regulates interphase MT-network architectures and possibly confers them unexpected functions.
Summary
Microtubules (MTs) are dynamic cytoskeleton filaments. They permanently transit between growth and shrinkage. This famous “dynamic instability” is governed by the addition and loss of tubulin dimers at their tips. In contrast to the tip, the MT lattice was considered to be a passive structure supporting intracellular transport. However, we recently found that MT lattice is dynamic and active! Actually, tubulin dimers can be exchanged with the cytoplasmic pool along the entire length of the MT. These incorporations can repair sites on the lattice that have been mechanically damaged. These repair sites protect the MTs from depolymerisation and increase the MT’s life span. This discovery opens up a new vista for understanding MT biology.
First, we will investigate the biochemical consequences of MT-lattice turnover. We hypothesise that tubulin turnover affects the recruitment of MAPs, motors and tubulin-modifying enzymes. These recruitments may feedback on lattice turnover and further regulate MT life span and functions.
Second, we will investigate the mechanical impact of the MT-lattice plasticity. Tubulin removal is likely to be associated with a local reduction of MT stiffness that can impact MT shape and the propagation of forces along the lattice. We anticipate that such effects will require us to reformulate the biophysical rules directing network architecture.
To achieve this, we will use reconstituted MT networks in vitro to investigate the molecular mechanism regulating MT-lattice plasticity, and cultured cells to test the physiological relevance of these mechanisms. In both approaches, microfabricated devices will be used to control the spatial boundary conditions directing MT self-organisation.
By exploring the hidden 90% of MT iceberg we aim to show that the MT lattice is a dynamic mechano-sensory structure which regulates interphase MT-network architectures and possibly confers them unexpected functions.
Max ERC Funding
1 998 227 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
Project acronym IFDG
Project INNOVATION, FIRM DYNAMICS AND GROWTH: what do we learn from French firm-level data?
Researcher (PI) Philippe AGHION
Host Institution (HI) COLLEGE DE FRANCE
Call Details Advanced Grant (AdG), SH1, ERC-2017-ADG
Summary This research project will confort theory and data to deepen our understanding of the mechanisms and policies of innovation, and the relationship between innovation, growth and social mobility. The underlying framework is the Schumpeterian theory of economic growth, where: (i) growth is generated by innovative entrepreneurs; (ii) entrepreneurial investments respond to incentives that are themselves shaped by economic policies and institutions; (iii) new innovations involves creative destruction. This project will explore new extensions of the Schumpeterian growth paradigm together with new firm-level and individual datasets to analyze the following questions : (a) the measurement of productivity growth and the extent to which measured TFP growth factors is correctly accounting for new innovation; (b) the relashionship between innovation and trade and more specifically the causal links from export and import to innovation, and the main channels through wich export and import affect innovation; (c) the effect of fiscal and institutional changes on entrepreneurship: in particular, how recent changes in the French legislation on self-employement have affected individual incentives to become self-employed, and differently so for different social or regional groups of individuals; (d) the relationship between creative destruction, inequality, and wellbeing: in particular, how does creative destruction (mesured by job or firm turnover) impact on social mobility (e.g measured by the probability of making it to top income brackets conditional upon a low initial income or a low parental income) and health. This approach can shed new light on important aspects of the growth process such as: the middle income trap, secular stagnation, the recent rise in top income inequality, and firm dynamics. Moreover, the paradigm can be used to think (or rethink) about growth policy design.
Summary
This research project will confort theory and data to deepen our understanding of the mechanisms and policies of innovation, and the relationship between innovation, growth and social mobility. The underlying framework is the Schumpeterian theory of economic growth, where: (i) growth is generated by innovative entrepreneurs; (ii) entrepreneurial investments respond to incentives that are themselves shaped by economic policies and institutions; (iii) new innovations involves creative destruction. This project will explore new extensions of the Schumpeterian growth paradigm together with new firm-level and individual datasets to analyze the following questions : (a) the measurement of productivity growth and the extent to which measured TFP growth factors is correctly accounting for new innovation; (b) the relashionship between innovation and trade and more specifically the causal links from export and import to innovation, and the main channels through wich export and import affect innovation; (c) the effect of fiscal and institutional changes on entrepreneurship: in particular, how recent changes in the French legislation on self-employement have affected individual incentives to become self-employed, and differently so for different social or regional groups of individuals; (d) the relationship between creative destruction, inequality, and wellbeing: in particular, how does creative destruction (mesured by job or firm turnover) impact on social mobility (e.g measured by the probability of making it to top income brackets conditional upon a low initial income or a low parental income) and health. This approach can shed new light on important aspects of the growth process such as: the middle income trap, secular stagnation, the recent rise in top income inequality, and firm dynamics. Moreover, the paradigm can be used to think (or rethink) about growth policy design.
Max ERC Funding
1 968 588 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
