Cadherin 4 assembles a family of color-preferring retinal circuits that respond to light offset

Retinal interneurons and projection neurons (retinal ganglion cells, RGCs) connect in specific combinations in a specialized neuropil called the inner plexiform layer (IPL). The IPL is divided into multiple sublaminae, with neurites of each neuronal type confined to one or a few layers. This laminar specificity is a major determinant of circuit specificity and circuit function. Using a combination of approaches, we show that RGCs targeting IPL sublaminae 1 and 3a (s1-s3a) express the cell adhesion molecule cadherin 4 (Cdh4). Using calcium imaging and iterative immunostaining, we classified Cdh4 RGCs into nine types that each encode unique aspects of dark visual stimuli. Cdh4 loss selectively disrupted the layer targeting of these RGCs, reduced their synaptic inputs from interneurons, and severely altered their visual responses. Overexpression of Cdh4 in other retinal neurons directed their neurites to s1-s3a through homophilic interactions. Taken together, these results demonstrate that Cdh4 is a novel layer-targeting system for nearly a quarter of all RGCs.