Serial Synapse Formation through Filopodial Competition for Synaptic Seeding Factors

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 1–2 “synaptogenic” filopodia suppress 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. The failure to form synapses can cause the destabilization and secondary retraction of axon terminals. Our model provides a filopodial “winner-takes-all” mechanism that ensures the formation of an appropriate number of synapses. [Display omitted] •Stochastic filopodia dynamics are required for robust synapse formation in fly brains•Only 1–2 filopodia at a time contain synaptic seeding factors and are synaptogenic•4D tracking and computational modeling support a serial synapse formation model•Synapse formation prevents axonal retraction How random axon filopodia dynamics lead to precise numbers of synaptic contacts during development is unknown. Özel et al. show, through live imaging and computational modeling, that a “winner-takes-all” distribution of synaptic seeding factors renders one filopodium at a time synaptogenic, thereby pacing development and ensuring robust connectivity.