Gamma-protocadherins regulate dendrite self-recognition and dynamics to drive self-avoidance

Abstract

Neurons form cell-type-specific morphologies that are shaped by cell-surface molecules and their cellular events governing dendrite growth. One growth rule is dendrite self-avoidance, whereby dendrites distribute uniformly within a neuron's territory by avoiding sibling branches. In mammalian neurons, dendrite self-avoidance is regulated by a large family of cell-recognition molecules called the clustered protocadherins (cPcdhs). Genetic and molecular studies suggest that the cPcdhs mediate homophilic recognition and repulsion between self-dendrites. However, this model has not been tested through direct investigation of self-avoidance during development. Here, we performed live imaging and four-dimensional (4D) quantifications of dendrite morphogenesis to define the dynamics and 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 dendritic protrusions that iteratively fill the growing arbor and contact and retract from nearby self-dendrites. Compared to non-self-contacting protrusions, self-contacting events have longer lifetimes, and a subset persists as loops. In the absence of the Pcdhgs, non-self-contacting dynamics are unaffected but self-contacting retractions are significantly diminished. Self-contacting 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 establish that the γ-Pcdhs mediate self-recognition and retraction between contacting sibling dendrites. Our results also illustrate how self-avoidance shapes stochastic and space-filling dendritic outgrowth for robust pattern formation in mammalian neurons.