TY - JOUR A1 - Jin, Eugene Jennifer A1 - Kiral, Ferdi Ridvan A1 - Ozel, Mehmet Neset A1 - Burchardt, Lara Sophie A1 - Osterland, Marc A1 - Epstein, Daniel A1 - Wolfenberg, Heike A1 - Prohaska, Steffen A1 - Hiesinger, Peter Robin T1 - Live Observation of Two Parallel Membrane Degradation Pathways at Axon Terminals JF - Current Biology N2 - Neurons are highly polarized cells that require continuous turnover of membrane proteins at axon terminals to develop, function, and survive. Yet, it is still unclear whether membrane protein degradation requires transport back to the cell body or whether degradation also occurs locally at the axon terminal, where live observation of sorting and degradation has remained a challenge. Here, we report direct observation of two cargo-specific membrane protein degradation mechanisms at axon terminals based on a live-imaging approach in intact Drosophila brains. We show that different acidification-sensing cargo probes are sorted into distinct classes of degradative ‘‘hub’’ compartments for synaptic vesicle proteins and plasma membrane proteins at axon terminals. Sorting and degradation of the two cargoes in the separate hubs are molecularly distinct. Local sorting of synaptic vesicle proteins for degradation at the axon terminal is, surprisingly, Rab7 independent, whereas sorting of plasma membrane proteins is Rab7 dependent. The cathepsin-like protease CP1 is specific to synaptic vesicle hubs, and its delivery requires the vesicle SNARE neuronal synaptobrevin. Cargo separation only occurs at the axon terminal, whereas degradative compartments at the cell body are mixed. These data show that at least two local, molecularly distinct pathways sort membrane cargo for degradation specifically at the axon terminal, whereas degradation can occur both at the terminal and en route to the cell body. Y1 - 2018 U6 - https://doi.org/10.1016/j.cub.2018.02.032 VL - 28 IS - 7 SP - 1027 EP - 1038.e4 ER - TY - JOUR A1 - Ozel, Mehmet Neset A1 - Kulkarni, Abhishek A1 - Hasan, Amr A1 - Brummer, Josephine A1 - Moldenhauer, Marian A1 - Daumann, Ilsa-Maria A1 - Wolfenberg, Heike A1 - Dercksen, Vincent J. A1 - Kiral, Ferdi Ridvan A1 - Weiser, Martin A1 - Prohaska, Steffen A1 - von Kleist, Max A1 - Hiesinger, Peter Robin T1 - Serial synapse formation through filopodial competition for synaptic seeding factors JF - Developmental Cell N2 - Following axon pathfinding, growth cones transition from stochastic filopodial exploration to the formation of a limited number of synapses. How the interplay of filopodia and synapse assembly ensures robust connectivity in the brain has remained a challenging problem. Here, we developed a new 4D analysis method for filopodial dynamics and a data-driven computational model of synapse formation for R7 photoreceptor axons in developing Drosophila brains. Our live data support a 'serial synapse formation' model, where at any time point only a single 'synaptogenic' filopodium suppresses the synaptic competence of other filopodia through competition for synaptic seeding factors. Loss of the synaptic seeding factors Syd-1 and Liprin-α leads to a loss of this suppression, filopodial destabilization and reduced synapse formation, which is sufficient to cause the destabilization of entire axon terminals. Our model provides a filopodial 'winner-takes-all' mechanism that ensures the formation of an appropriate number of synapses. Y1 - 2019 U6 - https://doi.org/10.1016/j.devcel.2019.06.014 VL - 50 IS - 4 SP - 447 EP - 461 ER -