Project acronym BRAINGAIN
Project NOVEL STRATEGIES FOR BRAIN REGENERATION
Researcher (PI) Andras Simon
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS3, ERC-2011-StG_20101109
Summary In contrast to mammals, newts possess exceptional capacities among vertebrates to rebuild complex structures, such as the brain. Our goal is to bridge the gap in the regenerative outcomes between newts and mammals. My group has made significant contributions towards this goal. We created a novel experimental system, which recapitulates central features of Parkinson’s disease in newts, and provides a unique model for understanding regeneration in the adult midbrain. We showed an unexpected but key feature of the newt brain that it is akin to the mammalian brain in terms of the extent of homeostatic cell turn over, but distinct in terms of its injury response, showing the regenerative capacity of the adult vertebrate brain by activating neurogenesis in normally quiescent regions. Further we established a critical role for the neurotransmitter dopamine in controlling quiescence in the midbrain, thereby preventing neurogenesis during homeostasis and terminating neurogenesis once the correct number of neurons has been produced during regeneration. Here we aim to identify key molecular pathways that regulate adult neurogenesis, to define lineage relationships between neuronal stem and progenitor cells, and to identify essential differences between newts and mammals. We will combine pharmacological modulation of neurotransmitter signaling with extensive cellular fate mapping approaches, and molecular manipulations. Ultimately we will test hypotheses derived from newt studies with mammalian systems including newt/mouse cross species complementation approaches. We expect that our findings will provide new regenerative strategies, and reveal fundamental aspects of cell fate determination, tissue growth, and tissue maintenance in normal and pathological conditions.
Summary
In contrast to mammals, newts possess exceptional capacities among vertebrates to rebuild complex structures, such as the brain. Our goal is to bridge the gap in the regenerative outcomes between newts and mammals. My group has made significant contributions towards this goal. We created a novel experimental system, which recapitulates central features of Parkinson’s disease in newts, and provides a unique model for understanding regeneration in the adult midbrain. We showed an unexpected but key feature of the newt brain that it is akin to the mammalian brain in terms of the extent of homeostatic cell turn over, but distinct in terms of its injury response, showing the regenerative capacity of the adult vertebrate brain by activating neurogenesis in normally quiescent regions. Further we established a critical role for the neurotransmitter dopamine in controlling quiescence in the midbrain, thereby preventing neurogenesis during homeostasis and terminating neurogenesis once the correct number of neurons has been produced during regeneration. Here we aim to identify key molecular pathways that regulate adult neurogenesis, to define lineage relationships between neuronal stem and progenitor cells, and to identify essential differences between newts and mammals. We will combine pharmacological modulation of neurotransmitter signaling with extensive cellular fate mapping approaches, and molecular manipulations. Ultimately we will test hypotheses derived from newt studies with mammalian systems including newt/mouse cross species complementation approaches. We expect that our findings will provide new regenerative strategies, and reveal fundamental aspects of cell fate determination, tissue growth, and tissue maintenance in normal and pathological conditions.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym DYNACOM
Project From Genome Integrity to Genome Plasticity:
Dynamic Complexes Controlling Once per Cell Cycle Replication
Researcher (PI) Zoi Lygerou
Host Institution (HI) PANEPISTIMIO PATRON
Call Details Starting Grant (StG), LS3, ERC-2011-StG_20101109
Summary Accurate genome duplication is controlled by multi-subunit protein complexes which associate with chromatin and dictate when and where replication should take place. Dynamic changes in these complexes lie at the heart of their ability to ensure the maintenance of genomic integrity. Defects in origin bound complexes lead to re-replication of the genome across evolution, have been linked to DNA-replication stress and may predispose for gene amplification events. Such genomic aberrations are central to malignant transformation.
We wish to understand how once per cell cycle replication is normally controlled within the context of the living cell and how defects in this control may result in loss of genome integrity and provide genome plasticity. To this end, live cell imaging in human cells in culture will be combined with genetic studies in fission yeast and modelling and in silico analysis.
The proposed research aims to:
1. Decipher the regulatory mechanisms which act in time and space to ensure once per cell cycle replication within living cells and how they may be affected by system aberrations, using functional live cell imaging.
2. Test whether aberrations in the licensing system may provide a selective advantage, through amplification of multiple genomic loci. To this end, a natural selection experiment will be set up in fission yeast .
3. Investigate how rereplication takes place along the genome in single cells. Is there heterogeneity amongst a population, leading to a plethora of different genotypes? In silico analysis of full genome DNA rereplication will be combined to single cell analysis in fission yeast.
4. Assess the relevance of our findings for gene amplification events in cancer. Does ectopic expression of human Cdt1/Cdc6 in cancer cells enhance drug resistance through gene amplification?
Our findings are expected to offer novel insight into mechanisms underlying cancer development and progression.
Summary
Accurate genome duplication is controlled by multi-subunit protein complexes which associate with chromatin and dictate when and where replication should take place. Dynamic changes in these complexes lie at the heart of their ability to ensure the maintenance of genomic integrity. Defects in origin bound complexes lead to re-replication of the genome across evolution, have been linked to DNA-replication stress and may predispose for gene amplification events. Such genomic aberrations are central to malignant transformation.
We wish to understand how once per cell cycle replication is normally controlled within the context of the living cell and how defects in this control may result in loss of genome integrity and provide genome plasticity. To this end, live cell imaging in human cells in culture will be combined with genetic studies in fission yeast and modelling and in silico analysis.
The proposed research aims to:
1. Decipher the regulatory mechanisms which act in time and space to ensure once per cell cycle replication within living cells and how they may be affected by system aberrations, using functional live cell imaging.
2. Test whether aberrations in the licensing system may provide a selective advantage, through amplification of multiple genomic loci. To this end, a natural selection experiment will be set up in fission yeast .
3. Investigate how rereplication takes place along the genome in single cells. Is there heterogeneity amongst a population, leading to a plethora of different genotypes? In silico analysis of full genome DNA rereplication will be combined to single cell analysis in fission yeast.
4. Assess the relevance of our findings for gene amplification events in cancer. Does ectopic expression of human Cdt1/Cdc6 in cancer cells enhance drug resistance through gene amplification?
Our findings are expected to offer novel insight into mechanisms underlying cancer development and progression.
Max ERC Funding
1 531 000 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym PAGE
Project The role of mRNA-processing bodies in ageing
Researcher (PI) Popi Syntichaki
Host Institution (HI) IDRYMA IATROVIOLOGIKON EREUNON AKADEMIAS ATHINON
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary Recently, we and others have revealed that, in the nematode Caenorhabditis elegans, reduction of protein synthesis rates in somatic cells extends lifespan. Based on this, we postulate that the molecular factors and mechanisms that control the mRNA metabolism in post-mitotic cells are critical determinants of ageing. This project will validate this hypothesis using C. elegans as main model system, but parallel studies in Saccharomyces cerevisiae and Drosophila melanogaster will prove the conservation of our observations. The cellular factors involved in mRNA metabolism (degradation/storage) are localized at specific particles in the cytoplasm of all eukaryotic cells, termed mRNA processing (P) bodies. Additionally, stress granules are cytoplasmic sites of mRNA-metabolism that are formed under stress conditions in mammalian cells. The objectives of this project include: -Monitoring of both P bodies and stress granules in adult worms and characterization of the age-related alterations in their profile, by immunostaining and real-time fluorescence imaging -Direct alterations in the expression of genes encoding factors of each particle in wild-type worms and analysis of the effects on lifespan and stress resistance -Comparison of the age-related changes in the profile of P bodies and stress granules between wild-type and long- or short-lived mutant worms -Direct alterations in the expression of genes encoding factors of each particle in worms with altered lifespan and investigation of the effects on lifespan and stress resistance -Observation of the age-related alterations in the profile of P bodies in yeast and flies, both in wild-type and long-lived strains. The rationale for this project is to provide insight into the modulation of ageing and stress resistance at the level of mRNA metabolism, which is a yet unexplored field of the biology of ageing and global stress response.
Summary
Recently, we and others have revealed that, in the nematode Caenorhabditis elegans, reduction of protein synthesis rates in somatic cells extends lifespan. Based on this, we postulate that the molecular factors and mechanisms that control the mRNA metabolism in post-mitotic cells are critical determinants of ageing. This project will validate this hypothesis using C. elegans as main model system, but parallel studies in Saccharomyces cerevisiae and Drosophila melanogaster will prove the conservation of our observations. The cellular factors involved in mRNA metabolism (degradation/storage) are localized at specific particles in the cytoplasm of all eukaryotic cells, termed mRNA processing (P) bodies. Additionally, stress granules are cytoplasmic sites of mRNA-metabolism that are formed under stress conditions in mammalian cells. The objectives of this project include: -Monitoring of both P bodies and stress granules in adult worms and characterization of the age-related alterations in their profile, by immunostaining and real-time fluorescence imaging -Direct alterations in the expression of genes encoding factors of each particle in wild-type worms and analysis of the effects on lifespan and stress resistance -Comparison of the age-related changes in the profile of P bodies and stress granules between wild-type and long- or short-lived mutant worms -Direct alterations in the expression of genes encoding factors of each particle in worms with altered lifespan and investigation of the effects on lifespan and stress resistance -Observation of the age-related alterations in the profile of P bodies in yeast and flies, both in wild-type and long-lived strains. The rationale for this project is to provide insight into the modulation of ageing and stress resistance at the level of mRNA metabolism, which is a yet unexplored field of the biology of ageing and global stress response.
Max ERC Funding
1 080 000 €
Duration
Start date: 2008-09-01, End date: 2014-08-31
Project acronym Triploid Block
Project Mechanisms of polyploidy-mediated postzygotic reproductive isolation
Researcher (PI) Claudia Köhler
Host Institution (HI) SVERIGES LANTBRUKSUNIVERSITET
Call Details Starting Grant (StG), LS3, ERC-2011-StG_20101109
Summary Polyploidization is a widespread phenomenon among plants and is considered a major speciation mechanism. Before becoming evolutionary successful, newly formed polyploids often have to overcome fertility bottlenecks, because mating with partners of lower ploidy causes incompatibilities in the endosperm leading to the formation of mainly non-viable progeny. This reproductive barrier is called the triploid block. Nevertheless, the most frequent route to polyploid formation is probably through unreduced gametes, suggesting that the triploid block can be overcome. Recent work from our laboratory uncovered a genetic pathway leading to unreduced gamete formation at high frequency and revealed that the triploid block is mainly caused by malfunction of Polycomb group (PcG) proteins. PcG proteins are evolutionary conserved proteins, which assemble into multimeric complexes with chromatin-modifying enzymatic activity, implicating epigenetic regulatory mechanisms as an important element of speciation. Here, I propose to unravel the underlying molecular mechanism(s) of the triploid block by identifying the responsible genes causing endosperm failure upon deregulation and their mechanism of regulation in response to interploidy crosses. I also plan to investigate whether genes that contribute to the triploid block are as well responsible for establishing interspecies incompatibilities within the Arabidopsis genus. This project will combine genetics, genomics and epigenomics and will make extensive use of knowledge and tools that we have been established in my laboratory over the recent years, making it likely that the proposed objectives can be achieved. The results of this project will be of interest to a broad scientific community, including biologists with a strong interest in epigenetic mechanisms as well as ecologists interested to understand mechanisms of plant speciation.
Summary
Polyploidization is a widespread phenomenon among plants and is considered a major speciation mechanism. Before becoming evolutionary successful, newly formed polyploids often have to overcome fertility bottlenecks, because mating with partners of lower ploidy causes incompatibilities in the endosperm leading to the formation of mainly non-viable progeny. This reproductive barrier is called the triploid block. Nevertheless, the most frequent route to polyploid formation is probably through unreduced gametes, suggesting that the triploid block can be overcome. Recent work from our laboratory uncovered a genetic pathway leading to unreduced gamete formation at high frequency and revealed that the triploid block is mainly caused by malfunction of Polycomb group (PcG) proteins. PcG proteins are evolutionary conserved proteins, which assemble into multimeric complexes with chromatin-modifying enzymatic activity, implicating epigenetic regulatory mechanisms as an important element of speciation. Here, I propose to unravel the underlying molecular mechanism(s) of the triploid block by identifying the responsible genes causing endosperm failure upon deregulation and their mechanism of regulation in response to interploidy crosses. I also plan to investigate whether genes that contribute to the triploid block are as well responsible for establishing interspecies incompatibilities within the Arabidopsis genus. This project will combine genetics, genomics and epigenomics and will make extensive use of knowledge and tools that we have been established in my laboratory over the recent years, making it likely that the proposed objectives can be achieved. The results of this project will be of interest to a broad scientific community, including biologists with a strong interest in epigenetic mechanisms as well as ecologists interested to understand mechanisms of plant speciation.
Max ERC Funding
1 447 596 €
Duration
Start date: 2011-10-01, End date: 2016-09-30
