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Friedrich Miescher Institute
Country: Switzerland
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203 Projects, page 1 of 41
  • Funder: SNSF Project Code: 188835
    Funder Contribution: 1,112,000
  • Funder: SNSF Project Code: 192642
    Funder Contribution: 986,184
  • Funder: EC Project Code: 666068
    Overall Budget: 2,200,680 EURFunder Contribution: 2,200,680 EUR

    Specificity in the ubiquitin-proteasome system is largely conferred by ubiquitin E3 ligases (E3s). Cullin-RING ligases (CRLs), constituting ~30% of all E3s in humans, mediate the ubiquitination of ~20% of the proteins degraded by the proteasome. CRLs are divided into seven families based on their cullin constituent. Each cullin binds a RING domain protein, and a vast repertoire of adaptor/substrate receptor modules, collectively creating more than 200 distinct CRLs. All CRLs are regulated by the COP9 signalosome (CSN), an eight-protein isopeptidase that removes the covalently attached activator, NEDD8, from the cullin. Independent of NEDD8 cleavage, CSN forms protective complexes with CRLs, which prevents destructive auto-ubiquitination. The integrity of the CSN-CRL system is crucially important for the normal cell physiology. Based on our previous work on CRL structures (Fischer, et al., Nature 2014; Fischer, et al., Cell 2011) and that of isolated CSN (Lingaraju et al., Nature 2014), We now intend to provide the underlying molecular mechanism of CRL regulation by CSN. Structural insights at atomic resolution, combined with in vitro and in vivo functional studies are designed to reveal (i) how the signalosome deneddylates and maintains the bound ligases in an inactive state, (ii) how the multiple CSN subunits bind to structurally diverse CRLs, and (iii) how CSN is itself subject to regulation by post-translational modifications or additional further factors. The ERC funding would allow my lab to pursue an ambitious interdisciplinary approach combining X-ray crystallography, cryo-electron microscopy, biochemistry and cell biology. This is expected to provide a unique molecular understanding of CSN action. Beyond ubiquitination, insight into this >13- subunit CSN-CRL assembly will allow examining general principles of multi-subunit complex action and reveal how the numerous, often essential, subunits contribute to complex function.

  • Funder: EC Project Code: 101032127
    Overall Budget: 191,149 EURFunder Contribution: 191,149 EUR

    Multicellular tissues, and ultimately complex organisms, are composed of multiple distinct cell types that differ in functional attributes. Such diversity in cell composition (i.e. phenotypic diversity) arises during development and regeneration, where progenitor cells differentiate along multiple cell fate lineages to form a heterogeneous population. While the molecular signals (i.e. cell states) that specify individual cell fates are widely studied, less is known about how multiple cell types can simultaneously emerge from a seemingly homogeneous population and which molecular mechanisms coordinate this process on a tissue-wide scale. Increasing evidence suggests that stochastic events, as opposed to hard-wired deterministic processes, are critical for emergence of heterogeneity. However, the molecular mechanisms that drive stochasticity and diversity in a mammalian tissue remain unknown, mainly due to a scarcity of tools to measure stochastic events in large numbers of single cells and to perturb cell-to-cell heterogeneity on a tissue level. Here I propose to use quantitative single-cell imaging, transcriptomic approaches, and optogenetic control of tissue heterogeneity to identify the molecular mechanisms driving phenotypic diversity. I will apply these techniques to mouse intestinal organoids, a multicellular system that recapitulates the intestinal epithelium. I hypothesize that variability in cell state (at the single-cell level) drives cell phenotypic diversity (at the tissue level). Different combinations of dynamic molecular signals within single cells may thereby pattern populations within a tissue to adopt specific fate outcomes. Gaining insight into the mechanisms of phenotypic diversity will answer fundamental questions in developmental and synthetic biology on the origins of cell diversity in multicellular tissues, how stochastic processes can ensure developmental robustness, and the maintenance of phenotypic equilibrium in homeostasis and disease.

  • Funder: EC Project Code: 692617
    Overall Budget: 2,500,000 EURFunder Contribution: 2,500,000 EUR

    Movement is the behavioral output of the nervous system. Animals carry out an enormous repertoire of distinct actions, spanning from seemingly simple repetitive tasks like walking to much more complex movements such as forelimb manipulation tasks. An important question is how neuronal circuits are organized and function to choose, maintain, adjust and terminate these many distinct motor behaviors. Recent technological advances in neuroscience have made it possible to begin to unravel the links between the organization of specific neuronal circuit elements in the CNS and the control of movement, a topic that will be central to this research program. While past work proposes that supraspinal centers in the brainstem are instrumental to the control of action diversification, little is known about how brainstem circuits translate movement intention to body control, how competing motor programs are selected, and how behavioral state influences movement control. The goal of this research project is to unravel the circuit blueprint of mouse descending motor pathways at a fine-scale level and to probe the intersection between revealed circuit organization and their behavioral function at many levels. The focus will be on studies on the interactions between brainstem neurons and spinal circuits to determine how initiation, duration, termination and selection of motor programs are implemented through specific neuronal subpopulations. Mapping descending connectivity matrices of motor circuits will serve as entry point and we will make use of state-of-the art intersectional technology including mouse genetics, viral approaches, in vivo neuronal recordings and activity manipulations of specific neuronal populations during behavior. Together, our project will elucidate the circuit organization and function of the descending motor output system and thereby uncover principles of how the nervous system generates diverse actions.

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