Project acronym FRU CIRCUIT
Project Neural basis of Drosophila mating behaviours
Researcher (PI) Barry Dickson
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary How does information processing in neural circuits generate behaviour? Answering this question requires identifying each of the distinct neuronal types that contributes to a behaviour, defining their anatomy and connectivity, and establishing causal relationships between their activity, the activity of other neurons in the circuit, and the behaviour. Here, I propose such an analysis of the neural circuits that guide Drosophila mating behaviours. The distinct mating behaviours of males and females are genetically pre-programmed, yet can also be modified by experience. The set of ~2000 neurons that express the fru gene have been intimately linked to both male and female mating behaviours. This set of neurons includes specific sensory, central, and motor neurons, at least some of which are directly connected. Male-specific fruM isoforms configure this circuit developmentally for male rather than female behaviour. In females, mating triggers a biochemical cascade that reconfigures the circuit for post-mating rather than virgin female behaviour. We estimate that there are ~100 distinct classes of fru neuron. Using genetic and optical tools, we aim to identify each distinct class of fru neuron and to define its anatomy and connectivity. By silencing or activating specific neurons, or changing their genetic sex, we will assess their contributions to male and female behaviours, and how these perturbations impinge on activity patterns in other fru neurons. We also aim to define how a specific experience can modify the physiological properties of these circuits, and how these changes in turn modulate mating behaviour. These studies will define the operating principles of these neural circuits, contributing to a molecules-to-systems explanation of Drosophila s mating behaviours.
Summary
How does information processing in neural circuits generate behaviour? Answering this question requires identifying each of the distinct neuronal types that contributes to a behaviour, defining their anatomy and connectivity, and establishing causal relationships between their activity, the activity of other neurons in the circuit, and the behaviour. Here, I propose such an analysis of the neural circuits that guide Drosophila mating behaviours. The distinct mating behaviours of males and females are genetically pre-programmed, yet can also be modified by experience. The set of ~2000 neurons that express the fru gene have been intimately linked to both male and female mating behaviours. This set of neurons includes specific sensory, central, and motor neurons, at least some of which are directly connected. Male-specific fruM isoforms configure this circuit developmentally for male rather than female behaviour. In females, mating triggers a biochemical cascade that reconfigures the circuit for post-mating rather than virgin female behaviour. We estimate that there are ~100 distinct classes of fru neuron. Using genetic and optical tools, we aim to identify each distinct class of fru neuron and to define its anatomy and connectivity. By silencing or activating specific neurons, or changing their genetic sex, we will assess their contributions to male and female behaviours, and how these perturbations impinge on activity patterns in other fru neurons. We also aim to define how a specific experience can modify the physiological properties of these circuits, and how these changes in turn modulate mating behaviour. These studies will define the operating principles of these neural circuits, contributing to a molecules-to-systems explanation of Drosophila s mating behaviours.
Max ERC Funding
2 492 164 €
Duration
Start date: 2009-07-01, End date: 2013-09-30
Project acronym GEMIS
Project Generalized Homological Mirror Symmetry and Applications
Researcher (PI) Ludmil Katzarkov
Host Institution (HI) UNIVERSITAT WIEN
Call Details Advanced Grant (AdG), PE1, ERC-2008-AdG
Summary Mirror symmetry arose originally in physics, as a duality between $N = 2$ superconformal field theories. Witten formulated a more mathematically accessible version, in terms of topological field theories. Both conformal and topological field theories can be defined axiomatically, but more interestingly, there are several geometric ways of constructing them. A priori, the mirror correspondence is not unique, and it does not necessarily remain within a single class of geometric models. The classical case relates $\sigma$-models, but in a more modern formulation, one has mirror dualities between different Landau-Ginzburg models, as well as between such models and $\sigma$-models; orbifolds should also be included in this. The simplest example would be the function $W: \C \rightarrow \C$, $W(x) = x^{n+1}$, which is self-mirror (up to dividing by the $\bZ/n+1$ symmetry group, in an orbifold sense). While the mathematics of the $\sigma$-model mirror correspondence is familiar by now, generalizations to Landau-Ginzburg theories are only beginning to be understood. Today it is clear that Homologcal Mirror Symmetry (HMS) as a categorical correspondence works and it is time for developing direct geometric applications to classical problems - rationality of algebraic varieties and Hodge conjecture. This the main goal of the proposal. But in order to attack the above problems we need to generalize HMS and explore its connection to new developments in modern Hodge theory. In order to carry the above program we plan to further already working team Vienna, Paris, Moscow, MIT.
Summary
Mirror symmetry arose originally in physics, as a duality between $N = 2$ superconformal field theories. Witten formulated a more mathematically accessible version, in terms of topological field theories. Both conformal and topological field theories can be defined axiomatically, but more interestingly, there are several geometric ways of constructing them. A priori, the mirror correspondence is not unique, and it does not necessarily remain within a single class of geometric models. The classical case relates $\sigma$-models, but in a more modern formulation, one has mirror dualities between different Landau-Ginzburg models, as well as between such models and $\sigma$-models; orbifolds should also be included in this. The simplest example would be the function $W: \C \rightarrow \C$, $W(x) = x^{n+1}$, which is self-mirror (up to dividing by the $\bZ/n+1$ symmetry group, in an orbifold sense). While the mathematics of the $\sigma$-model mirror correspondence is familiar by now, generalizations to Landau-Ginzburg theories are only beginning to be understood. Today it is clear that Homologcal Mirror Symmetry (HMS) as a categorical correspondence works and it is time for developing direct geometric applications to classical problems - rationality of algebraic varieties and Hodge conjecture. This the main goal of the proposal. But in order to attack the above problems we need to generalize HMS and explore its connection to new developments in modern Hodge theory. In order to carry the above program we plan to further already working team Vienna, Paris, Moscow, MIT.
Max ERC Funding
1 060 800 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym MEMFOLD
Project New approaches to the study of membrane-protein folding in vivo and in silico
Researcher (PI) Gunnar Von Heijne
Host Institution (HI) STOCKHOLMS UNIVERSITET
Call Details Advanced Grant (AdG), LS1, ERC-2008-AdG
Summary Membrane proteins are central players in many if not most cellular processes: cell-cell interaction, signal transduction, nerve conduction, small molecule transport, macromolecular trafficking, etc. A growing number of high-resolution membrane protein structures provide important insights not only into function but also into the general structural constraints imposed by the lipid bilayer. In contrast, almost no information is available concerning how membrane proteins fold in vivo. Mainly, this is because of a lack of suitable assays to follow the folding process. The main objective of this proposal is to develop a broad range of new methods, largely based on chemical-biology approaches combined with protein engineering, to study membrane protein insertion, folding, and assembly in vivo or under in vivo-like conditions. We will aim for quantitative studies whenever possible. Questions we will address include: What are the in vivo kinetics of transmembrane-helix integration? What are the energetics of membrane insertion of non-natural amino acid side chains with physico-chemical properties distinct from those of the 20 natural amino acids? What kinds of residue-residue interactions drive interactions between transmembrane helices and between membrane protein subunits? How should we best design and verify novel interacting transmembrane helices? Given the importance of membrane proteins in both basic and applied biological research, we expect that a deeper understanding of the molecular interactions that drive their folding and stabilize their structure in vivo will have a major impact across many areas of molecular life science.
Summary
Membrane proteins are central players in many if not most cellular processes: cell-cell interaction, signal transduction, nerve conduction, small molecule transport, macromolecular trafficking, etc. A growing number of high-resolution membrane protein structures provide important insights not only into function but also into the general structural constraints imposed by the lipid bilayer. In contrast, almost no information is available concerning how membrane proteins fold in vivo. Mainly, this is because of a lack of suitable assays to follow the folding process. The main objective of this proposal is to develop a broad range of new methods, largely based on chemical-biology approaches combined with protein engineering, to study membrane protein insertion, folding, and assembly in vivo or under in vivo-like conditions. We will aim for quantitative studies whenever possible. Questions we will address include: What are the in vivo kinetics of transmembrane-helix integration? What are the energetics of membrane insertion of non-natural amino acid side chains with physico-chemical properties distinct from those of the 20 natural amino acids? What kinds of residue-residue interactions drive interactions between transmembrane helices and between membrane protein subunits? How should we best design and verify novel interacting transmembrane helices? Given the importance of membrane proteins in both basic and applied biological research, we expect that a deeper understanding of the molecular interactions that drive their folding and stabilize their structure in vivo will have a major impact across many areas of molecular life science.
Max ERC Funding
1 999 999 €
Duration
Start date: 2009-04-01, End date: 2015-03-31
Project acronym STEMRENEWAL
Project Identification of a new mechanism of stem cell self-renewal; direct implications on self-repair and tumor initiating cells in the brain
Researcher (PI) Patrik Ernfors
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary The self-renewing nature of stem cells is a consequence of their ability to proliferate indefinitely while maintaining pluripotency. Mechanisms of pluripotency are well known but mechanisms controlling stem cell proliferation are unknown. Proliferation of somatic cells takes place in G1 cell cycle phase. We have identified that embryonic and peripheral neural stem cell proliferation is regulated by an entirely new mechanism involving chromatin remodeling and operating in the S/G2 phase of the cell cycle (Andang et al., Nature 2009). This involves the DNA damage response (DDR) pathway proteins. The DDR pathway is activated physiologically by GABA acting by the GABAA receptor leading to Cl- influx, cell swelling, and by unknown mechanism, activation of the PI3K related kinases ATR/ATM which phosphorylates histone H2AX. Combined, the data suggests that the DDR pathway is operating in a ligand-dependent manner under normal physiological conditions and that it may serve as a new molecular mechanism regulating cell proliferation in eukaryotic cells. We propose a homeostatic mechanism of stem cell proliferation where negative feedback control of the cell cycle adjusts stem cell numbers. The demonstration of normal, physiological, ligand-induced activation of these pathways in stem cell niches opens fundamentally new insight into the mechanisms of stem cell proliferation and surveillance against cancer. Once characterized, we propose that these mechanisms may be exploited to induce self repair following brain damage and to manipulate cell survival in tumor initiating cells of the brain (that share many characteristics with stem cells). The potential benefit of this proposed research could be vast, involving potentially a unifying mechanism how all stem cell niches in the embryo and in the adult individual is regulated and can be manipulated.
Summary
The self-renewing nature of stem cells is a consequence of their ability to proliferate indefinitely while maintaining pluripotency. Mechanisms of pluripotency are well known but mechanisms controlling stem cell proliferation are unknown. Proliferation of somatic cells takes place in G1 cell cycle phase. We have identified that embryonic and peripheral neural stem cell proliferation is regulated by an entirely new mechanism involving chromatin remodeling and operating in the S/G2 phase of the cell cycle (Andang et al., Nature 2009). This involves the DNA damage response (DDR) pathway proteins. The DDR pathway is activated physiologically by GABA acting by the GABAA receptor leading to Cl- influx, cell swelling, and by unknown mechanism, activation of the PI3K related kinases ATR/ATM which phosphorylates histone H2AX. Combined, the data suggests that the DDR pathway is operating in a ligand-dependent manner under normal physiological conditions and that it may serve as a new molecular mechanism regulating cell proliferation in eukaryotic cells. We propose a homeostatic mechanism of stem cell proliferation where negative feedback control of the cell cycle adjusts stem cell numbers. The demonstration of normal, physiological, ligand-induced activation of these pathways in stem cell niches opens fundamentally new insight into the mechanisms of stem cell proliferation and surveillance against cancer. Once characterized, we propose that these mechanisms may be exploited to induce self repair following brain damage and to manipulate cell survival in tumor initiating cells of the brain (that share many characteristics with stem cells). The potential benefit of this proposed research could be vast, involving potentially a unifying mechanism how all stem cell niches in the embryo and in the adult individual is regulated and can be manipulated.
Max ERC Funding
2 492 593 €
Duration
Start date: 2009-03-01, End date: 2014-02-28
