Gamma-Protocadherins regulate filopodia self-recognition and dynamics to drive dendrite self-avoidance

SUMMARY Neurons form cell type-specific morphologies that are shaped by molecular cues and their cellular events governing dendrite growth. One growth rule is distributing dendrites uniformly within a neuron’s territory by avoiding sibling or ‘self’ branches. In mammalian neurons, dendrite self-avoidance is regulated by the clustered Protocadherins (cPcdhs), a large family of recognition molecules. Genetic and molecular studies suggest that the cPcdhs mediate homophilic recognition and repulsion between self-dendrites but this model has not been tested through direct investigation of self-avoidance during development. Here we performed live imaging and 4D quantifications of dendrite morphogenesis to define the cPcdh-dependent mechanisms of self-avoidance. We focused on the mouse retinal starburst amacrine cell (SAC), which requires the gamma-Pcdhs ( Pcdhgs ) and self/non-self recognition to establish a stereotypic radial morphology while permitting dendritic interactions with neighboring SACs. Through morphogenesis, SACs extend a transient population of dynamic filopodia that fill the growing arbor and contact nearby self-dendrites. Compared to non-self-contacting filopodia, self-contacting events have longer lifetimes and a subset persists as filopodia bridges. In the absence of the Pcdhgs , non-self-contacting filopodia dynamics are unaffected but self-contact-induced retractions are significantly diminished. Filopodia bridges accumulate, leading to the bundling of dendritic processes and disruption to the arbor shape. By tracking dendrite self-avoidance in real-time, our findings demonstrate that the γ-Pcdhs selectively mediate contact-induced retractions upon filopodia self-recognition. Our results also illustrate how self-avoidance shapes the stochastic and space-filling behaviors of filopodia for robust dendritic pattern formation in mammalian neurons. HIGHLIGHTS Dendrite self-avoidance proceeds through interstitial filopodia and contact-induced retractions between sibling processes. Self-contacting filopodia exhibit longer lifetimes and a subset of contacts persist. Pcdhgs selectively regulate self-contact-induced retractions. Loss of Pcdhgs and filopodia self-avoidance disrupts dendritic arbor shape.