Project Details
Projekt
Autophagic regulation of synapse formation in the Drosophila brain
Applicant
Professor Dr. Peter Robin Hiesinger
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Cell Biology
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 447288260
Autophagy (referring to macroautophagy in this proposal) in the nervous system was first described as a maintenance mechanism in adult neurons, based on the observation of adultonset degeneration in largely normally developed atg5 or atg7 mutant mouse brains1,2. More detailed studies subsequently revealed developmental defects specific to synapse formation in mice, worms and flies3-5. Key to these developmental roles of autophagy are the timing and location of autophagosome formation and how they affect what substrates are locally degraded. In RP7, we propose to analyze such highly localized and, compared to bulk autophagy in the cell body, typically rare autophagosome formation events and their function at developing synapses inside the living fly brain using multiphoton imaging. This work is motivated by findings from the first funding period, where we characterized the roles of developmental autophagy in the presynaptic terminals of two very different neurons in the fly brain: in the non-branched axon terminals of R7 photoreceptor neurons, autophagosome formation destabilizes synaptogenic filopodia and thereby regulates synapse numbers and partner recruitment. By contrast, in the highly branched axons of dorsal cluster neurons (DCNs), autophagy is actively suppressed during synapse formation, and its de-repression leads to the degradation of nascent synapses during brain development. Hence, local regulation of autophagy in these two neuron types serves distinct roles during synapse formation with different substrate specificity. We hypothesize that highly localized autophagy more generally can play diverse and highly specific developmental roles during synapse formation, depending on when and where exactly autophagosome formation is triggered in a specific neuron. RP7 is devised to test this hypothesis by experimentally asking whether different neuron types principally employ local autophagy in unique, context-specific ways, or whether there are common themes. In preparation for the second funding period, we have thus begun to investigate the role of autophagy in three additional interneuron types with unique developmental and morphological features. Furthermore, we have identified a role for Atg8-dependent phagocytosis in glia cells in the regulation of neuronal synapses in the developing brain. Hence, both cell-autonomous and non-autonomous mechanisms employing autophagic machinery partake in the regulation of synapse formation during brain development. In RP7, we will dissect these different roles in selected neuron types to understand the local, context-specific roles autophagic mechanisms play during brain development.
DFG Programme
Research Units
