phosphatase; plasticity; Drosophila; synapse; neurodegeneration; signaling; kinase
Stephan Raiko, Goellner Bernd, Moreno Eliza, Frank C. Andrew, Hugenschmidt Tabea, Genoud Christel, Aberle Hermann, Pielage Jan (2015), Hierarchical Microtubule Organization Controls Axon Caliber and Transport and Determines Synaptic Structure and Stability, in Developmental Cell
, 33(1), 5-21.
Siegenthaler Dominique, Enneking Eva-Maria, Moreno Eliza, Pielage Jan (2015), L1CAM/Neuroglian controls the axon–axon interactions establishing layered and lobular mushroom body architecture, in Journal of Cell Biology
, 208(7), 1003-1018.
Bulat Victoria, Rast Melanie, Pielage Jan (2014), Presynaptic CK2 promotes synapse organization and stability by targeting Ankyrin2, in The Journal of Cell Biology
, 204(1), 77-94.
The precise wiring of the nervous system is essential for all aspects of brain function including sensory perception, execution of motor tasks and learning and memory. Any adaptation of information processing within neuronal circuits occurs at the level of synaptic connections, the basic unit of the nervous system. External signals like for example learning paradigms can induce either a change in synaptic efficacy (functional plasticity) or a change in synaptic connectivity (structural plasticity). Recent in vivo live imaging studies in behaving animals provided evidence that structural synaptic plasticity is induced in response to external stimuli and might represent the cellular correlate of learning and memory. Furthermore, these studies demonstrated that synapse assembly and disassembly are tightly controlled and executed in a local manner to ensure stability and function of the circuit at all times. At the molecular level, these processes require precise control by signaling cascades that induce fast and reversible changes mediated for example through posttranslational phosphorylation. Any disruption of these signaling cascades by genetic mutations will cause an inappropriate loss of synaptic connections, a key feature of progressive neurodegenerative diseases. Despite the importance of these processes we know very little regarding the molecular mechanisms inducing and executing changes in synaptic connectivity in response to developmental and activity-dependent signals. To address these questions, we established a high-resolution assay that allows the systematic identification of regulators of synapse assembly and disassembly. We are using the Drosophila neuromuscular junction as a model system as this allows the combination of large-scale genetic screens with high resolution imaging approaches to identify changes in synapse development and maintenance. In preliminary work we used this system to screen the entire kinome and phosphatome of Drosophila for regulators of synapse plasticity. In the proposed project we will focus on three main candidates controlling distinct steps of synapse development including synapse formation, active zone organization and stability. We aim to identify the activation, function and targets of these kinases and phosphatases to elucidate the complete signaling cascades controlling these processes. The combination of in vivo rescue assays with chemical genetic screens and live imaging will allow us to gain unique insights into the molecular mechanisms underlying synapse assembly and disassembly and to identify novel, biologically relevant targets. Importantly, our past work has demonstrated that the molecular mechanisms underlying synapse development and plasticity are highly conserved between Drosophila and vertebrates. This conservation has been demonstrated for mechanisms controlling learning and memory related changes and mechanisms underlying progressive neurodegenerative disorders.The proposed project will significantly advance our understanding of the molecular signaling pathways controlling essential aspects of synapse biology and reveal new principles underlying the regulation of synapse function and plasticity relevant for neuronal circuit development and disease.