Project acronym BARRAGE
Project Cell compartmentalization, individuation and diversity
Researcher (PI) Yves Barral
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Advanced Grant (AdG), LS3, ERC-2009-AdG
Summary Asymmetric cell division is a key mechanism for the generation of cell diversity in eukaryotes. During this process, a polarized mother cell divides into non-equivalent daughters. These may differentially inherit fate determinants, irreparable damages or age determinants. Our aim is to decipher the mechanisms governing the individualization of daughters from each other. In the past ten years, our studies identified several lateral diffusion barriers located in the plasma membrane and the endoplasmic reticulum of budding yeast. These barriers all restrict molecular exchanges between the mother cell and its bud, and thereby compartmentalize the cell already long before its division. They play key roles in the asymmetric segregation of various factors. On one side, they help maintain polarized factors into the bud. Thereby, they reinforce cell polarity and sequester daughter-specific fate determinants into the bud. On the other side they prevent aging factors of the mother from entering the bud. Hence, they play key roles in the rejuvenation of the bud, in the aging of the mother, and in the differentiation of mother and daughter from each other. Recently, we accumulated evidence that some of these barriers are subject to regulation, such as to help modulate the longevity of the mother cell in response to environmental signals. Our data also suggest that barriers help the mother cell keep traces of its life history, thereby contributing to its individuation and adaption to the environment. In this project, we will address the following questions: 1 How are these barriers assembled, functioning, and regulated? 2 What type of differentiation processes are they involved in? 3 Are they conserved in other eukaryotes, and what are their functions outside of budding yeast? These studies will shed light into the principles underlying and linking aging, rejuvenation and differentiation.
Summary
Asymmetric cell division is a key mechanism for the generation of cell diversity in eukaryotes. During this process, a polarized mother cell divides into non-equivalent daughters. These may differentially inherit fate determinants, irreparable damages or age determinants. Our aim is to decipher the mechanisms governing the individualization of daughters from each other. In the past ten years, our studies identified several lateral diffusion barriers located in the plasma membrane and the endoplasmic reticulum of budding yeast. These barriers all restrict molecular exchanges between the mother cell and its bud, and thereby compartmentalize the cell already long before its division. They play key roles in the asymmetric segregation of various factors. On one side, they help maintain polarized factors into the bud. Thereby, they reinforce cell polarity and sequester daughter-specific fate determinants into the bud. On the other side they prevent aging factors of the mother from entering the bud. Hence, they play key roles in the rejuvenation of the bud, in the aging of the mother, and in the differentiation of mother and daughter from each other. Recently, we accumulated evidence that some of these barriers are subject to regulation, such as to help modulate the longevity of the mother cell in response to environmental signals. Our data also suggest that barriers help the mother cell keep traces of its life history, thereby contributing to its individuation and adaption to the environment. In this project, we will address the following questions: 1 How are these barriers assembled, functioning, and regulated? 2 What type of differentiation processes are they involved in? 3 Are they conserved in other eukaryotes, and what are their functions outside of budding yeast? These studies will shed light into the principles underlying and linking aging, rejuvenation and differentiation.
Max ERC Funding
2 200 000 €
Duration
Start date: 2010-05-01, 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 CHROMOCOND
Project A molecular view of chromosome condensation
Researcher (PI) Frank Uhlmann
Host Institution (HI) CANCER RESEARCH UK LBG
Call Details Advanced Grant (AdG), LS3, ERC-2009-AdG
Summary Eukaryotic cells inherit much of their genomic information in the form of chromosomes during cell division. Centimetre-long DNA molecules are packed into micrometer-sized chromosomes to enable this process. How DNA is organised within mitotic chromosomes is still largely unknown. A key structural protein component of mitotic chromosomes, implicated in their compaction, is the condensin complex. In this proposal, we aim to elucidate the molecular architecture of mitotic chromosomes, taking advantage of new genomic techniques and the relatively simple genome organisation of yeast model systems. We will place particular emphasis on elucidating the contribution of the condensin complex, and the cell cycle regulation of its activities, in promoting chromosome condensation. Our previous work has provided genome-wide maps of condensin binding to budding and fission yeast chromosomes. We will continue to decipher the molecular determinants for condensin binding. To investigate how condensin mediates DNA compaction, we propose to generate chromosome-wide DNA/DNA proximity maps. Our approach will be an extension of the chromosome conformation capture (3C) technique. High throughput sequencing of interaction points has provided a first glimpse of the interactions that govern chromosome condensation. The role that condensin plays in promoting these interactions will be investigated. The contribution of condensin s ATP-dependent activities, and cell cycle-dependent post-translational modifications, will be studied. This will be complemented by mathematical modelling of the condensation process. In addition to chromosome condensation, condensin is required for resolution of sister chromatids in anaphase. We will develop an assay to study the catenation status of sister chromatids and how condensin may contribute to their topological resolution.
Summary
Eukaryotic cells inherit much of their genomic information in the form of chromosomes during cell division. Centimetre-long DNA molecules are packed into micrometer-sized chromosomes to enable this process. How DNA is organised within mitotic chromosomes is still largely unknown. A key structural protein component of mitotic chromosomes, implicated in their compaction, is the condensin complex. In this proposal, we aim to elucidate the molecular architecture of mitotic chromosomes, taking advantage of new genomic techniques and the relatively simple genome organisation of yeast model systems. We will place particular emphasis on elucidating the contribution of the condensin complex, and the cell cycle regulation of its activities, in promoting chromosome condensation. Our previous work has provided genome-wide maps of condensin binding to budding and fission yeast chromosomes. We will continue to decipher the molecular determinants for condensin binding. To investigate how condensin mediates DNA compaction, we propose to generate chromosome-wide DNA/DNA proximity maps. Our approach will be an extension of the chromosome conformation capture (3C) technique. High throughput sequencing of interaction points has provided a first glimpse of the interactions that govern chromosome condensation. The role that condensin plays in promoting these interactions will be investigated. The contribution of condensin s ATP-dependent activities, and cell cycle-dependent post-translational modifications, will be studied. This will be complemented by mathematical modelling of the condensation process. In addition to chromosome condensation, condensin is required for resolution of sister chromatids in anaphase. We will develop an assay to study the catenation status of sister chromatids and how condensin may contribute to their topological resolution.
Max ERC Funding
2 076 126 €
Duration
Start date: 2010-04-01, End date: 2015-03-31
Project acronym CILIARYDISEASE
Project Deciphering mechanisms of ciliary disease
Researcher (PI) Heiko Lickert
Host Institution (HI) HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Call Details Starting Grant (StG), LS3, ERC-2009-StG
Summary Ciliopathies are pleiotropic diseases with a wide spectrum of human phenotypes. These include cyst formation in the liver and pancreas, respiratory disorders and a predisposition to diabetes and cancer. The pleiotropic nature of these disorders may reflect the many roles cilia play in physiology and signalling, highlighting the clinical importance of understanding their function in organ development and homeostasis. Despite the biological importance of cilia and decades of research, many aspects of cilia assembly and disassembly remain elusive. The earliest steps of cilia assembly involve conversion of the centrosome into a basal body, which anchors the cilia to the plasma membrane. Odf2 is one of the only proteins known to be important for this process, thus Ofd2 mutant cells lack cilia. During cell cycle re-entry primary cilia disassemble, the basal body dislodges from the plasma membrane and duplicates to serve as the mitotic centrosome. We recently identified Pitchfork, which functions in basal body-to-centrosome conversion and regulates embryonic patterning. The overall aim of this proposal is to better understand the cellular and bio-molecular mechanisms underlying ciliary disease. We will conditionally delete Odf2 and Pitchfork during embryogenesis and organogenesis. This will reveal the different requirements for the process of cilia assembly and disassembly in embryonic development, organ formation and homeostasis. The phenotypes will be analyzed at all levels of complexity. Subcellular imaging and identification of protein interaction partners will uncover the molecular basis of cilia assembly and disassembly. In summary, this project will decipher mechanisms underlying a wide spectrum of human ciliary disease and will open new avenues of clinical research.
Summary
Ciliopathies are pleiotropic diseases with a wide spectrum of human phenotypes. These include cyst formation in the liver and pancreas, respiratory disorders and a predisposition to diabetes and cancer. The pleiotropic nature of these disorders may reflect the many roles cilia play in physiology and signalling, highlighting the clinical importance of understanding their function in organ development and homeostasis. Despite the biological importance of cilia and decades of research, many aspects of cilia assembly and disassembly remain elusive. The earliest steps of cilia assembly involve conversion of the centrosome into a basal body, which anchors the cilia to the plasma membrane. Odf2 is one of the only proteins known to be important for this process, thus Ofd2 mutant cells lack cilia. During cell cycle re-entry primary cilia disassemble, the basal body dislodges from the plasma membrane and duplicates to serve as the mitotic centrosome. We recently identified Pitchfork, which functions in basal body-to-centrosome conversion and regulates embryonic patterning. The overall aim of this proposal is to better understand the cellular and bio-molecular mechanisms underlying ciliary disease. We will conditionally delete Odf2 and Pitchfork during embryogenesis and organogenesis. This will reveal the different requirements for the process of cilia assembly and disassembly in embryonic development, organ formation and homeostasis. The phenotypes will be analyzed at all levels of complexity. Subcellular imaging and identification of protein interaction partners will uncover the molecular basis of cilia assembly and disassembly. In summary, this project will decipher mechanisms underlying a wide spectrum of human ciliary disease and will open new avenues of clinical research.
Max ERC Funding
1 449 640 €
Duration
Start date: 2010-02-01, End date: 2015-01-31
Project acronym DNADEMETHYLASE
Project Functions and mechanism of active DNA demethylation
Researcher (PI) Heinz Christof Niehrs
Host Institution (HI) INSTITUT FUR MOLEKULARE BIOLOGIE GGMBH
Call Details Advanced Grant (AdG), LS3, ERC-2009-AdG
Summary Epigenetic gene regulation is of central importance for development and disease. Despite dramatic progress in epigenetics during the past decade, DNA demethylation remains one of the last big frontiers and very little is known about it. DNA demethylation is a widespread phenomenon and occurs in plants as well as in animals, during development, in the adult, and during somatic cell reprogramming of pluripotency genes. The molecular identity of the DNA demethylase in animal cells remained unresolved and has hampered progress in the field for decades. In 2007 we published that Growth Arrest and DNA Damage 45 a (Gadd45a) is a key player in active DNA demethylation, which opened new avenues in the study of this elusive process. The goal of this project is to further analyze the mechanism of DNA demethylation as well as the role played by Gadd45 in development. Given the many unresolved questions in this burgeoning field, our work promises to be ground-breaking and therefore have a profound impact in unraveling one of the least understood processes of gene regulation. Specifically we will address the following points. I) The biological role of Gadd45 mediated DNA demethylation in mouse embryos and adults is unknown. We have obtained mouse mutants for Gadd45a,b, and g and we will analyze them for developmental defects and dissect the methylation regulation of relevant genes. II) The targeting mechanism by which Gadd45 is binding to and demethylating specific sites in the genome is a central unresolved issue. We have identified a candidate DNA binding protein interacting with Gadd45 and we will analyze its role in site specific targeting of DNA demethylation in vitro and in mouse. III) We found that Gadd45 is an RNA binding protein and we will therefore analyze how non-coding RNAs are involved in targeting and/or activating Gadd45 during DNA demethylation.
Summary
Epigenetic gene regulation is of central importance for development and disease. Despite dramatic progress in epigenetics during the past decade, DNA demethylation remains one of the last big frontiers and very little is known about it. DNA demethylation is a widespread phenomenon and occurs in plants as well as in animals, during development, in the adult, and during somatic cell reprogramming of pluripotency genes. The molecular identity of the DNA demethylase in animal cells remained unresolved and has hampered progress in the field for decades. In 2007 we published that Growth Arrest and DNA Damage 45 a (Gadd45a) is a key player in active DNA demethylation, which opened new avenues in the study of this elusive process. The goal of this project is to further analyze the mechanism of DNA demethylation as well as the role played by Gadd45 in development. Given the many unresolved questions in this burgeoning field, our work promises to be ground-breaking and therefore have a profound impact in unraveling one of the least understood processes of gene regulation. Specifically we will address the following points. I) The biological role of Gadd45 mediated DNA demethylation in mouse embryos and adults is unknown. We have obtained mouse mutants for Gadd45a,b, and g and we will analyze them for developmental defects and dissect the methylation regulation of relevant genes. II) The targeting mechanism by which Gadd45 is binding to and demethylating specific sites in the genome is a central unresolved issue. We have identified a candidate DNA binding protein interacting with Gadd45 and we will analyze its role in site specific targeting of DNA demethylation in vitro and in mouse. III) We found that Gadd45 is an RNA binding protein and we will therefore analyze how non-coding RNAs are involved in targeting and/or activating Gadd45 during DNA demethylation.
Max ERC Funding
2 376 000 €
Duration
Start date: 2010-06-01, End date: 2015-05-31
Project acronym ESED
Project Evolution of sensory organ morphology: genetic analysis of eye size evolution in Drosophila
Researcher (PI) Alistair Peter Mcgregor
Host Institution (HI) OXFORD BROOKES UNIVERSITY
Call Details Starting Grant (StG), LS3, ERC-2009-StG
Summary Living organisms exhibit great variation in size and shape, and display many morphological innovations. Recent progress has been made in identifying the genetic basis for the evolution of some traits but there remains a paucity of knowledge concerning the evolution of complex morphological traits, and how the underlying changes arose and spread in populations. This proposal will address this by establishing a research program to investigate the genetic basis for the evolution of intra- and inter- specific differences in a complex sensory organ, the insect compound eye. Drosophila mauritiana has significantly larger eyes than its sibling species D. simulans. However, there is also considerable eye size variation between D. simulans populations. Taking advantage of our knowledge of eye development in flies, this proposal will describe the developmental basis for eye size differences and investigate the number and distribution of photoreceptor subtypes (which are sensitive to different light wavelengths) between species and populations with eye size variation. In addition, the proposal will take advantage of cutting edge methods to map the molecular basis for eye size evolution between D. mauritiana and D. simulans, and compare this to the genetic architecture of eye size differences within D. simulans. Population genetic approaches will then be applied to test evolved sequences for directional selection. Thus, this project will not only reveal the genetic changes in development underlying the evolution of eye size and resolve the contribution of standing genetic variation for eye size differences within species to differences between species, but also establish this trait as a model for future studies of morphological evolution.
Summary
Living organisms exhibit great variation in size and shape, and display many morphological innovations. Recent progress has been made in identifying the genetic basis for the evolution of some traits but there remains a paucity of knowledge concerning the evolution of complex morphological traits, and how the underlying changes arose and spread in populations. This proposal will address this by establishing a research program to investigate the genetic basis for the evolution of intra- and inter- specific differences in a complex sensory organ, the insect compound eye. Drosophila mauritiana has significantly larger eyes than its sibling species D. simulans. However, there is also considerable eye size variation between D. simulans populations. Taking advantage of our knowledge of eye development in flies, this proposal will describe the developmental basis for eye size differences and investigate the number and distribution of photoreceptor subtypes (which are sensitive to different light wavelengths) between species and populations with eye size variation. In addition, the proposal will take advantage of cutting edge methods to map the molecular basis for eye size evolution between D. mauritiana and D. simulans, and compare this to the genetic architecture of eye size differences within D. simulans. Population genetic approaches will then be applied to test evolved sequences for directional selection. Thus, this project will not only reveal the genetic changes in development underlying the evolution of eye size and resolve the contribution of standing genetic variation for eye size differences within species to differences between species, but also establish this trait as a model for future studies of morphological evolution.
Max ERC Funding
1 225 040 €
Duration
Start date: 2010-01-01, End date: 2014-12-31
Project acronym EVO500
Project Origin of a cell differentiation mechanism and its evolution over 500 million years of life on land
Researcher (PI) Liam Dolan
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Advanced Grant (AdG), LS3, ERC-2009-AdG
Summary The evolution of the first rooting systems approximately 470 million years ago was a critical event in the history of life on Earth because it allowed the growth of complex multicellular eukaryotic photosynthetic organisms – plants - on the surface of the land. Rooting systems are important because they facilitate the uptake of every chemical element in the plant body with the exception of carbon. The root systems of the
first land plants (liverworts) comprised a mass of unicellular tip-growing filaments (rhizoids) that grew from the plant surface into the soil. All root systems that evolved since then similarly comprise a system of tipgrowing filamentous cells located at the interface between the plant and the soil, indicating that the differentiation of filamentous root cells has been critical for root function for the past 470 million years. This proposal aims to characterize the origin and evolution of this essential cellular differentiation process. The proposed research is in three parts:
First we propose to define the mechanism that controlled the development of the first land plant root system by identifying genes that control liverwort rooting system (rhizoids) development and
characterizing their regulatory interactions.
Second we propose to determine if the mechanism that controlled the development of the first land
plant root system was inherited from algal ancestors.
Third we propose to characterize the mechanism that controls filamentous root hair growth in
Arabidopsis in response to environmental factors, and determine if it is conserved among land
plants.
In combination, these experiments will define the genetic mechanisms underpinning the development and evolution of one of the fundamental developmental processes in land plants.
Summary
The evolution of the first rooting systems approximately 470 million years ago was a critical event in the history of life on Earth because it allowed the growth of complex multicellular eukaryotic photosynthetic organisms – plants - on the surface of the land. Rooting systems are important because they facilitate the uptake of every chemical element in the plant body with the exception of carbon. The root systems of the
first land plants (liverworts) comprised a mass of unicellular tip-growing filaments (rhizoids) that grew from the plant surface into the soil. All root systems that evolved since then similarly comprise a system of tipgrowing filamentous cells located at the interface between the plant and the soil, indicating that the differentiation of filamentous root cells has been critical for root function for the past 470 million years. This proposal aims to characterize the origin and evolution of this essential cellular differentiation process. The proposed research is in three parts:
First we propose to define the mechanism that controlled the development of the first land plant root system by identifying genes that control liverwort rooting system (rhizoids) development and
characterizing their regulatory interactions.
Second we propose to determine if the mechanism that controlled the development of the first land
plant root system was inherited from algal ancestors.
Third we propose to characterize the mechanism that controls filamentous root hair growth in
Arabidopsis in response to environmental factors, and determine if it is conserved among land
plants.
In combination, these experiments will define the genetic mechanisms underpinning the development and evolution of one of the fundamental developmental processes in land plants.
Max ERC Funding
2 463 835 €
Duration
Start date: 2010-10-01, End date: 2015-09-30
Project acronym FPMICROGLIA
Project Towards a dynamic quantitative understanding of neuronal microglial interactions
Researcher (PI) Francesca Peri
Host Institution (HI) EUROPEAN MOLECULAR BIOLOGY LABORATORY
Call Details Starting Grant (StG), LS3, ERC-2009-StG
Summary A significant proportion of neurons in the brain undergo programmed cell death. In order to prevent the diffusion of damaging degradation products, dying neurons are quickly collected by microglia, specialised phagocytes that are resident in the brain. Despite the importance of these cells in several neuronal pathologies, many fundamental questions concerning microglial-neuronal interactions remain unaddressed. How these cells collectively ensure that the entire brain is surveyed and how they react to damage with high precision is still entirely unknown. Recent findings suggest that diffusible molecules such as lipids and nucleotides could attract microglia in response to neuronal apoptosis and injury, respectively. While these molecules can trigger dynamic changes in microglia motility in vitro, elucidating how their activity is controlled within the intact brain, both in space and time, remains the most important challenge in understanding this fascinating biological problem. We aim to further exploit the massive imaging potential of the transparent zebrafish embryo for studying microglial biology in vivo. By combining forward and reverse genetic approaches with quantitative imaging technology, we will directly address the mechanisms underlying the attraction of microglia towards apoptotic, sick and injured neurons. For the first time, we will define the collective behaviour of an entire microglial network within an intact brain under both physiological and pathological conditions.
Summary
A significant proportion of neurons in the brain undergo programmed cell death. In order to prevent the diffusion of damaging degradation products, dying neurons are quickly collected by microglia, specialised phagocytes that are resident in the brain. Despite the importance of these cells in several neuronal pathologies, many fundamental questions concerning microglial-neuronal interactions remain unaddressed. How these cells collectively ensure that the entire brain is surveyed and how they react to damage with high precision is still entirely unknown. Recent findings suggest that diffusible molecules such as lipids and nucleotides could attract microglia in response to neuronal apoptosis and injury, respectively. While these molecules can trigger dynamic changes in microglia motility in vitro, elucidating how their activity is controlled within the intact brain, both in space and time, remains the most important challenge in understanding this fascinating biological problem. We aim to further exploit the massive imaging potential of the transparent zebrafish embryo for studying microglial biology in vivo. By combining forward and reverse genetic approaches with quantitative imaging technology, we will directly address the mechanisms underlying the attraction of microglia towards apoptotic, sick and injured neurons. For the first time, we will define the collective behaviour of an entire microglial network within an intact brain under both physiological and pathological conditions.
Max ERC Funding
663 090 €
Duration
Start date: 2010-03-01, End date: 2014-08-31
Project acronym GEMELLI
Project Gene networks controlling embryonic polarity, regulation and twinning
Researcher (PI) Claudio Daniel Stern
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Advanced Grant (AdG), LS3, ERC-2009-AdG
Summary Much of what we know about how embryos determine their axes of symmetry comes from research in invertebrates (mainly Drosophila) and cold-blooded vertebrates (mainly Xenopus). In both cases, polarity is set up by the localisation of maternal determinants in the cytoplasm of the fertilised egg. These determinants are inherited differentially by daughter cells, leading them to acquire different fates, which effectively fixes the axes of the embryo by the 8 cell stage. In contrast, in amniotes (reptiles, birds and mammals) embryonic polarity remains plastic until much later, just before gastrulation, when the embryo may contain as many as 50,000 cells. If an embryo at this stage is cut into fragments, each fragment can generate a complete embryo. This property, called "embryonic regulation", is thought to be responsible for the generation of monozygotic (identical) and conjoined ( Siamese ) twins in humans and other amniotes. We know almost nothing about how polarity is determined in higher vertebrates or about the mechanisms of embryonic regulation and twinning. This project uses a multi-disciplinary systems approach to reveal the gene interaction network controlling polarity, regulation and twinning. The project will also generate a mathematical model of early development or "virtual embryo", allowing prediction of experimental outcomes and clinical scenarios.
Summary
Much of what we know about how embryos determine their axes of symmetry comes from research in invertebrates (mainly Drosophila) and cold-blooded vertebrates (mainly Xenopus). In both cases, polarity is set up by the localisation of maternal determinants in the cytoplasm of the fertilised egg. These determinants are inherited differentially by daughter cells, leading them to acquire different fates, which effectively fixes the axes of the embryo by the 8 cell stage. In contrast, in amniotes (reptiles, birds and mammals) embryonic polarity remains plastic until much later, just before gastrulation, when the embryo may contain as many as 50,000 cells. If an embryo at this stage is cut into fragments, each fragment can generate a complete embryo. This property, called "embryonic regulation", is thought to be responsible for the generation of monozygotic (identical) and conjoined ( Siamese ) twins in humans and other amniotes. We know almost nothing about how polarity is determined in higher vertebrates or about the mechanisms of embryonic regulation and twinning. This project uses a multi-disciplinary systems approach to reveal the gene interaction network controlling polarity, regulation and twinning. The project will also generate a mathematical model of early development or "virtual embryo", allowing prediction of experimental outcomes and clinical scenarios.
Max ERC Funding
1 997 899 €
Duration
Start date: 2010-06-01, End date: 2016-02-29
