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 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 CENTROSTEMCANCER
Project Investigating the link between centrosomes, stem cells and cancer
Researcher (PI) Renata Homem De Gouveia Xavier De Basto
Host Institution (HI) INSTITUT CURIE
Call Details Starting Grant (StG), LS3, ERC-2009-StG
Summary Centrosomes are cytoplasmic organelles found in most animal cells with important roles in polarity establishment and maintenance. Theodor Boveri s pioneering work first suggested that extra-centrosomes could contribute to genetic instability and consequently to tumourigenesis. Although many human tumours do exhibit centrosome amplification (extra centrosomes) or centrosome abnormalities, the exact contribution of centrosomes to tumour initiation in vertebrate organisms remains to be determined. I have recently showed that Drosophila flies carrying extra-centrosomes, following the over-expression of the centriole replication kinase Sak, did not exhibit chromosome segregation errors and were able to maintain a stable diploid genome over many generations. Surprisingly, however, neural stem cells fail frequently to align the mitotic spindle with their polarity axis during asymmetric division. Moreover, I have found that centrosome amplification is permissive to tumour formation in flies. So far, however, we do not know the molecular mechanisms that allow transformation when extra centrosomes are present and elucidating these mechanisms is the aim of the work presented in this proposal. Here, I describe a series of complementary approaches that will help us to decipher the link between centrosomes, stem cells and tumour biology. In addition, I wish to pursue the original observations made in Drosophila and investigate the consequences of centrosome amplification in mammals.
Summary
Centrosomes are cytoplasmic organelles found in most animal cells with important roles in polarity establishment and maintenance. Theodor Boveri s pioneering work first suggested that extra-centrosomes could contribute to genetic instability and consequently to tumourigenesis. Although many human tumours do exhibit centrosome amplification (extra centrosomes) or centrosome abnormalities, the exact contribution of centrosomes to tumour initiation in vertebrate organisms remains to be determined. I have recently showed that Drosophila flies carrying extra-centrosomes, following the over-expression of the centriole replication kinase Sak, did not exhibit chromosome segregation errors and were able to maintain a stable diploid genome over many generations. Surprisingly, however, neural stem cells fail frequently to align the mitotic spindle with their polarity axis during asymmetric division. Moreover, I have found that centrosome amplification is permissive to tumour formation in flies. So far, however, we do not know the molecular mechanisms that allow transformation when extra centrosomes are present and elucidating these mechanisms is the aim of the work presented in this proposal. Here, I describe a series of complementary approaches that will help us to decipher the link between centrosomes, stem cells and tumour biology. In addition, I wish to pursue the original observations made in Drosophila and investigate the consequences of centrosome amplification in mammals.
Max ERC Funding
1 550 000 €
Duration
Start date: 2010-01-01, End date: 2015-06-30
Project acronym D-END
Project Telomeres: from the DNA end replication problem to the control of cell proliferation
Researcher (PI) Maria Teresa Teixeira Fernandes Bernardo
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), LS1, ERC-2010-StG_20091118
Summary Linear chromosomes of eukaryotes end with telomeres that ensure their stability. Because of the inability of semi-conservative DNA replication machinery to fully replicate DNA ends, telomeres require dedicated mechanisms to be duplicated and their length is eroded at each cell division. For this reason, telomeres constitute molecular clocks that determine cell proliferation potential in eukaryotes. Strikingly, we have shown recently that it is the shortest telomere in the cell that determines the onset of replicative senescence. This project aims a complete and detailed dissection of the in vivo DNA-end replication problem and the deep understanding of its impact for cell division capability. Specifically my goals are (1) the determination of the exact structures that result from the replication of DNA extremities, (2) the examination of the activities operating at the shortest telomere that triggers replicative senescence and (3) the investigation of the correspondence between telomere molecular structure and cell proliferation state at individual cell scale. To achieve this, I will undertake in Saccharomyces cerevisiae original and innovative single-molecule and single-cell approaches, that, in combination with genome-wide screens and sophisticated cellular settings, will allow to track and challenge a specified telomere of defined length. I anticipate that this work will lead to an in-depth understanding of how telomeres are replicated and how they enable the control of cell proliferation in eukaryotic cells, a matter at the intersection of the fundamentals of molecular genetics, cell biology of aging and oncology.
Summary
Linear chromosomes of eukaryotes end with telomeres that ensure their stability. Because of the inability of semi-conservative DNA replication machinery to fully replicate DNA ends, telomeres require dedicated mechanisms to be duplicated and their length is eroded at each cell division. For this reason, telomeres constitute molecular clocks that determine cell proliferation potential in eukaryotes. Strikingly, we have shown recently that it is the shortest telomere in the cell that determines the onset of replicative senescence. This project aims a complete and detailed dissection of the in vivo DNA-end replication problem and the deep understanding of its impact for cell division capability. Specifically my goals are (1) the determination of the exact structures that result from the replication of DNA extremities, (2) the examination of the activities operating at the shortest telomere that triggers replicative senescence and (3) the investigation of the correspondence between telomere molecular structure and cell proliferation state at individual cell scale. To achieve this, I will undertake in Saccharomyces cerevisiae original and innovative single-molecule and single-cell approaches, that, in combination with genome-wide screens and sophisticated cellular settings, will allow to track and challenge a specified telomere of defined length. I anticipate that this work will lead to an in-depth understanding of how telomeres are replicated and how they enable the control of cell proliferation in eukaryotic cells, a matter at the intersection of the fundamentals of molecular genetics, cell biology of aging and oncology.
Max ERC Funding
1 498 504 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym DOME
Project Dissecting a Novel Mechanism of Cell Motility
Researcher (PI) Tâm Mignot
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), LS3, ERC-2010-StG_20091118
Summary Cell motility is essential for many biological processes, including development and pathogenesis. Thus, the
molecular mechanisms underlying this process have been intensively studied in many cell systems, for
example, leukocytes, amoeba and even bacteria. Intriguingly, bacteria are also able to move across solid
surfaces (gliding motility) like eukaryotic cells by a process that has remained largely mysterious. The
emergence of bacterial cell biology: the discovery that the bacterial cell also has a dynamic cytoskeleton and
specialized subcellular regions now provides new research angles to study the motility mechanism. Using
cell biology approaches, we previously suggested that the mechanism may be akin to acto-myosin-based
motility in eukaryotic cells and proposed that bacterial focal adhesion complexes also power locomotion. In
this project, we propose two complementary research axes to define both the mechanism and its spatial
regulation in the cell at molecular resolution.
Using the model motility bacterium Myxococcus xanthus, we first propose to develop a “toolbox” of
biophysical and cell biology assays to analyze the motility process. Specifically, we will construct a Traction
Force Microscopy assay designed to image the motility forces directly by live moving cells and use
microfluidics to quantitate the secretion of a mucus that may participate directly in the motility process.
These assays, combined with a newly developed laser trap system to visualize dynamic focal adhesions in
the cell envelope, will be instrumental not only to define new features of the motility process, but also to
study the function of novel motility genes which may encode the components of the elusive motility engine.
This way, we hope to establish the mechanism and structure function relationships within an entirely novel
motility machinery.
In a second part, we propose to investigate the mechanism that controls a polarity switch, allowing M.
xanthus cells to change their direction of movement. We have previously shown that dynamic motility
protein pole-to-pole oscillations convert the initial leading cell pole into the lagging pole. Here, we propose
that like in a eukaryotic cells, a bacterial counterpart of small GTPases of the Ras superfamily, MglA
controls the polarity cycle. To test this hypothesis, we will study both the MglA upstream regulation and the
MglA downstream effectors. We thus hope to establish a model of dynamic polarity control in a bacterial
Summary
Cell motility is essential for many biological processes, including development and pathogenesis. Thus, the
molecular mechanisms underlying this process have been intensively studied in many cell systems, for
example, leukocytes, amoeba and even bacteria. Intriguingly, bacteria are also able to move across solid
surfaces (gliding motility) like eukaryotic cells by a process that has remained largely mysterious. The
emergence of bacterial cell biology: the discovery that the bacterial cell also has a dynamic cytoskeleton and
specialized subcellular regions now provides new research angles to study the motility mechanism. Using
cell biology approaches, we previously suggested that the mechanism may be akin to acto-myosin-based
motility in eukaryotic cells and proposed that bacterial focal adhesion complexes also power locomotion. In
this project, we propose two complementary research axes to define both the mechanism and its spatial
regulation in the cell at molecular resolution.
Using the model motility bacterium Myxococcus xanthus, we first propose to develop a “toolbox” of
biophysical and cell biology assays to analyze the motility process. Specifically, we will construct a Traction
Force Microscopy assay designed to image the motility forces directly by live moving cells and use
microfluidics to quantitate the secretion of a mucus that may participate directly in the motility process.
These assays, combined with a newly developed laser trap system to visualize dynamic focal adhesions in
the cell envelope, will be instrumental not only to define new features of the motility process, but also to
study the function of novel motility genes which may encode the components of the elusive motility engine.
This way, we hope to establish the mechanism and structure function relationships within an entirely novel
motility machinery.
In a second part, we propose to investigate the mechanism that controls a polarity switch, allowing M.
xanthus cells to change their direction of movement. We have previously shown that dynamic motility
protein pole-to-pole oscillations convert the initial leading cell pole into the lagging pole. Here, we propose
that like in a eukaryotic cells, a bacterial counterpart of small GTPases of the Ras superfamily, MglA
controls the polarity cycle. To test this hypothesis, we will study both the MglA upstream regulation and the
MglA downstream effectors. We thus hope to establish a model of dynamic polarity control in a bacterial
Max ERC Funding
1 437 693 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
Project acronym ECCENTRIC
Project Epigenetic challenges in centromere inheritance during the cell cycle
Researcher (PI) Geneviève Almouzni - Pettinotti
Host Institution (HI) INSTITUT CURIE
Call Details Advanced Grant (AdG), LS1, ERC-2009-AdG
Summary Studies concerning the mechanism of DNA replication have advanced our understanding of genetic transmission through multiple cell cycles. Recent work has shed light on possible means to ensure the stable transmission of information beyond just DNA and the concept of epigenetic inheritance has emerged. Considering chromatin-based information, key candidates have arisen as epigenetic marks including DNA and histone modifications, histone variants, non-histone chromatin proteins, nuclear RNA as well as higher-order chromatin organization. Thus, understanding the dynamics and stability of these marks following disruptive events during replication and repair and throughout the cell cycle becomes of critical importance for the maintenance of any given chromatin state. To approach these issues, we propose to study the maintenance of heterochromatin at centromeres, key chromosomal regions for the proper chromosome segregation. Our current goal is to access to the sophisticated mechanisms that have evolved in order to facilitate inheritance of epigenetic marks not only at the replication fork, but also at other stages of the cell cycle, during repair and development. Beyond inheritance of DNA methylation, understanding how inheritance of histone variants and their modifications can be controlled either coupled or not coupled to DNA replication will be a major focus of this project. Our studies will build on the expertise and tools developed over the years in a strategy that integrates molecular, cellular, and biochemical approaches. This will be combined with the use of new technologies to monitor cell cycle (Fucci), protein dynamics (SNAP-Tagging) together with single molecule analysis involving DNA and chromatin combing. We wish to define a possible framework for an understanding of both the stability and reversibility of epigenetic marks and their dynamics at centromeres. These lessons may teach us general principles of inheritance of epigenetic states.
Summary
Studies concerning the mechanism of DNA replication have advanced our understanding of genetic transmission through multiple cell cycles. Recent work has shed light on possible means to ensure the stable transmission of information beyond just DNA and the concept of epigenetic inheritance has emerged. Considering chromatin-based information, key candidates have arisen as epigenetic marks including DNA and histone modifications, histone variants, non-histone chromatin proteins, nuclear RNA as well as higher-order chromatin organization. Thus, understanding the dynamics and stability of these marks following disruptive events during replication and repair and throughout the cell cycle becomes of critical importance for the maintenance of any given chromatin state. To approach these issues, we propose to study the maintenance of heterochromatin at centromeres, key chromosomal regions for the proper chromosome segregation. Our current goal is to access to the sophisticated mechanisms that have evolved in order to facilitate inheritance of epigenetic marks not only at the replication fork, but also at other stages of the cell cycle, during repair and development. Beyond inheritance of DNA methylation, understanding how inheritance of histone variants and their modifications can be controlled either coupled or not coupled to DNA replication will be a major focus of this project. Our studies will build on the expertise and tools developed over the years in a strategy that integrates molecular, cellular, and biochemical approaches. This will be combined with the use of new technologies to monitor cell cycle (Fucci), protein dynamics (SNAP-Tagging) together with single molecule analysis involving DNA and chromatin combing. We wish to define a possible framework for an understanding of both the stability and reversibility of epigenetic marks and their dynamics at centromeres. These lessons may teach us general principles of inheritance of epigenetic states.
Max ERC Funding
2 490 483 €
Duration
Start date: 2010-06-01, End date: 2015-12-31
Project acronym FORCEFULACTIN
Project Coordinated regulation of actin dynamics in cell motility and morphogenesis : from molecules to reconstituted biomimetic assays
Researcher (PI) Marie-France Carlier Épouse Pantaloni
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS1, ERC-2009-AdG
Summary An impressive variety of motile and morphogenetic processes are driven by site-directed polarized asssembly of actin filaments. In the past ten years, breathtaking advances coming from cell biology, cell biophysics, and biochemistry have brought insight into the molecular bases for production of force and movement by site-directed actin polymerization. Yet, we do not know, with the detail sufficient to understand how force is produced, by which molecular mechanisms the filaments are nucleated or created by branching. We do not know by which elementary steps insertional polymerization of barbed ends of filaments against the membrane is performed by different protein machineries, nor how these machineries work in a coordinated fashion. Here we propose a multiscale and interdisciplinary approach of the mechanisms used by the major actin nucleators to organize the motile response of actin. The elementary reactions involved in the processive walk of formin at the growing barbed ends of filaments and the role of ATP hydrolysis in force production will be analyzed by a combination of biochemical solution studies and physical methods using functionalized GUVs and optical tweezers. The multifunctionality of WH2 domains involved in actin sequestration, filament nucleation severing and processive elongation will be similarly examined in an interdisciplinary perspective from structural biology at atomic resolution to physics at the mesoscopic scale. Biochemical and structural methods and single molecule measurements (TIRFM) will shed light into the elementary steps and structural mechanism of filament branching. Biomimetic assays with functionalized GUVs associated with biophysical methods like FRAP or fluorescence correlation spectroscopy will elucidate how different filament initiating machineries segregate in the membrane as a consequence of their interactions with growing filaments and function in a coordinated fashion during actin-based motility.
Summary
An impressive variety of motile and morphogenetic processes are driven by site-directed polarized asssembly of actin filaments. In the past ten years, breathtaking advances coming from cell biology, cell biophysics, and biochemistry have brought insight into the molecular bases for production of force and movement by site-directed actin polymerization. Yet, we do not know, with the detail sufficient to understand how force is produced, by which molecular mechanisms the filaments are nucleated or created by branching. We do not know by which elementary steps insertional polymerization of barbed ends of filaments against the membrane is performed by different protein machineries, nor how these machineries work in a coordinated fashion. Here we propose a multiscale and interdisciplinary approach of the mechanisms used by the major actin nucleators to organize the motile response of actin. The elementary reactions involved in the processive walk of formin at the growing barbed ends of filaments and the role of ATP hydrolysis in force production will be analyzed by a combination of biochemical solution studies and physical methods using functionalized GUVs and optical tweezers. The multifunctionality of WH2 domains involved in actin sequestration, filament nucleation severing and processive elongation will be similarly examined in an interdisciplinary perspective from structural biology at atomic resolution to physics at the mesoscopic scale. Biochemical and structural methods and single molecule measurements (TIRFM) will shed light into the elementary steps and structural mechanism of filament branching. Biomimetic assays with functionalized GUVs associated with biophysical methods like FRAP or fluorescence correlation spectroscopy will elucidate how different filament initiating machineries segregate in the membrane as a consequence of their interactions with growing filaments and function in a coordinated fashion during actin-based motility.
Max ERC Funding
2 434 195 €
Duration
Start date: 2010-05-01, End date: 2015-10-31
Project acronym GROLEO
Project The Genetics and Physiology of Growth and Size Determination
Researcher (PI) Pierre Leopold
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Advanced Grant (AdG), LS3, ERC-2010-AdG_20100317
Summary Animal growth is a complex process that is intimately linked to the developmental program in order to form fit adults with proper size and proportions. Genetics is an important determinant of growth, exemplified by the role of local diffusible molecules in setting organ proportions for a given species. In addition to this genetic control, organisms use adaptation mechanisms allowing modulating the size of individuals according to environmental cues, among which nutrition. Therefore, sophisticated cross-talks between local and global cues are at play for the determination of the final size of an individual. The major objective of this project is to tackle the mechanisms involved in coupling growth control with environmental cues, as well as the mechanisms participating in growth arrest and the determination of final size.
Our project proposes a blend of physiological and genetic approaches on the Drosophila model, with the use of tissue-targeted loss-of-function to unravel some of the important cross-talks existing between organs for the control of growth at the global level. We will develop these approaches to (i) unravel the molecular nature of tissue cross-talks involved in nutrient sensing and the control of insulin/IGF secretion; (ii) tackle the feed-back mechanisms linking the developmental clock to the growing state of tissues and organs.
These projects should bring new contributions in two separate fields related to growth control, Developmental Biology and Physiology, in an attempt to merge these complementary approaches into a broader vision of this fascinating biological question.
Summary
Animal growth is a complex process that is intimately linked to the developmental program in order to form fit adults with proper size and proportions. Genetics is an important determinant of growth, exemplified by the role of local diffusible molecules in setting organ proportions for a given species. In addition to this genetic control, organisms use adaptation mechanisms allowing modulating the size of individuals according to environmental cues, among which nutrition. Therefore, sophisticated cross-talks between local and global cues are at play for the determination of the final size of an individual. The major objective of this project is to tackle the mechanisms involved in coupling growth control with environmental cues, as well as the mechanisms participating in growth arrest and the determination of final size.
Our project proposes a blend of physiological and genetic approaches on the Drosophila model, with the use of tissue-targeted loss-of-function to unravel some of the important cross-talks existing between organs for the control of growth at the global level. We will develop these approaches to (i) unravel the molecular nature of tissue cross-talks involved in nutrient sensing and the control of insulin/IGF secretion; (ii) tackle the feed-back mechanisms linking the developmental clock to the growing state of tissues and organs.
These projects should bring new contributions in two separate fields related to growth control, Developmental Biology and Physiology, in an attempt to merge these complementary approaches into a broader vision of this fascinating biological question.
Max ERC Funding
2 500 000 €
Duration
Start date: 2011-07-01, End date: 2016-06-30
Project acronym RETROGENOMICS
Project Mechanisms of retrotransposition in humans and consequences on cancer genomic plasticity
Researcher (PI) Gael Pierre Varam Cristofari
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS1, ERC-2009-StG
Summary Retrotransposons are a class of highly repetitive sequences, which are very abundant in the human genome. They disperse by an RNA-based copy-and-paste mechanism, called retrotransposition. This process can drive profound genome rearrangements. Although generally silent, they are expressed in germ cells, in the early embryo, and in embryonic stem cells, which occasionally results in genetic diseases. Retrotransposons are also massively re-expressed in the large majority of cancers, but the importance and consequences of retrotransposition in human tumors have been poorly studied. Somatic retrotransposition is difficult to track in human tissue due to the highly repetitive and dispersed nature of these elements. Thus the questions we wish to address in this research proposal are the following: (i) What cellular pathways control retrotransposon copy number? This will be achieved by combining functional genomics and proteomics approaches to identify positive and negative regulators of retrotransposition in humans. (ii) What are the molecular mechanisms of retrotransposons replication? To answer this question, we will develop a cell-free assay that will contain the complete retrotransposition machinery. (iii) How retrotransposons participate in the normal and pathological remodeling of the human genome? To this purpose we are currently developing innovative approaches to track retrotransposition events in clinical samples, especially in tumor samples. Since LINE-1 elements (L1) are the most active and autonomous retroelements in our genome, we focus, at the moment, our investigations on this family. Understanding how the activity of retrotransposons is controlled will impact our knowledge of the mechanisms that lead to new genetic diseases or to cancer progression. Since mobile genetic elements are becoming important tools in insertional mutagenesis or gene-transfer technologies in mammals, our work should also help to improve their use in mammalian functional genomics.
Summary
Retrotransposons are a class of highly repetitive sequences, which are very abundant in the human genome. They disperse by an RNA-based copy-and-paste mechanism, called retrotransposition. This process can drive profound genome rearrangements. Although generally silent, they are expressed in germ cells, in the early embryo, and in embryonic stem cells, which occasionally results in genetic diseases. Retrotransposons are also massively re-expressed in the large majority of cancers, but the importance and consequences of retrotransposition in human tumors have been poorly studied. Somatic retrotransposition is difficult to track in human tissue due to the highly repetitive and dispersed nature of these elements. Thus the questions we wish to address in this research proposal are the following: (i) What cellular pathways control retrotransposon copy number? This will be achieved by combining functional genomics and proteomics approaches to identify positive and negative regulators of retrotransposition in humans. (ii) What are the molecular mechanisms of retrotransposons replication? To answer this question, we will develop a cell-free assay that will contain the complete retrotransposition machinery. (iii) How retrotransposons participate in the normal and pathological remodeling of the human genome? To this purpose we are currently developing innovative approaches to track retrotransposition events in clinical samples, especially in tumor samples. Since LINE-1 elements (L1) are the most active and autonomous retroelements in our genome, we focus, at the moment, our investigations on this family. Understanding how the activity of retrotransposons is controlled will impact our knowledge of the mechanisms that lead to new genetic diseases or to cancer progression. Since mobile genetic elements are becoming important tools in insertional mutagenesis or gene-transfer technologies in mammals, our work should also help to improve their use in mammalian functional genomics.
Max ERC Funding
1 874 000 €
Duration
Start date: 2010-01-01, End date: 2014-12-31
Project acronym SEENANOLIFEINACTION
Project Real-Time Studies of Biological NanoMachines in Action by NMR
Researcher (PI) Jerome Boisbouvier
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), LS1, ERC-2010-StG_20091118
Summary a
Summary
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Max ERC Funding
1 398 392 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
