Mechanism and function of dendritic self-avoidance and self/non-self discrimination in the mammalian nervous system


Dendritic and axonal arbors of many neuronal types exhibit self-avoidance, a phenomenon in which branches repel each other. This process ensures that individual neurons cover all parts of their territory uniformly. Some neurons that self-avoid overlap with neighbors of the same type, suggesting that nominally identical neurons are immune to each other’s repellent forces, a phenomenon called self/non-self discrimination. Here, I describe the roles of the 22 clustered gamma-Protocadherin (Pcdhg) recognition molecules in dendritic self-avoidance and self/non-self discrimination of mammalian neurons, and the roles of these phenomena in a retinal circuit. First, I present studies showing that Pcdhgs are necessary for dendritic self-avoidance and self/non-self discrimination of retinal starburst amacrine cells (SACs) and cerebellar Purkinje cells. Using loss and gain of function experiments, we showed that no single Pcdhg isoform is necessary and any Pcdhg isoform is sufficient to mediate self-avoidance. However, forcing neighboring SACs to express a single Pcdhg decreases their overlap. Thus, Pcdhg diversity is necessary for SACs to avoid their own dendrites, but interact with their neighbors (self/non-self discrimination). Second, I describe the roles of self-avoidance and self/non-self discrimination in the function of a retinal direction-selective circuit that depends on SACs. Dendrites of SACs compute directional motion and endow classes of retinal ganglion cells with this property by inhibiting them asymmetrically during visual motion. In addition, SACs form inhibitory synapses in order to sharpen each other’s direction-selectivity. I present findings that elucidate the roles self-avoidance and self/non-self discrimination in the function of this direction-selective circuit: (1) In the absence of self-avoidance, SACs form synapses with their own dendrites. (2) In the absence of self/non-self discrimination, SACs form few synapses with each other, (3) Loss of either self-avoidance or self/non-self discrimination degrades directional responses of ganglion cells. Lastly, I describe initial efforts to understand the combinatorial roles of all clustered Pcdh family members, which also include 14 alpha- and 22 beta-Protocadherins (Pcdhas and Pcdhbs, respectively). We used CRISPR-mediated genome engineering to generate Pcdha/Pcdhg double mutants. Initial analysis shows that their defects are more striking than those of either Pcdha or Pcdhg mutants, suggesting redundancy between these two subclusters.

PhD thesis