Afferent control of horizontal cell morphology revealed by genetic respecification of rods and cones

The first inhibitory interneurons of the retina, the horizontal cells, stratify within the outer plexiform layer, extending dendritic terminals that connect to the pedicles of cone photoreceptors and an axon terminal system contacting the spherules of rod photoreceptors. How the horizontal cells acquire this morphology is unknown, but instructive interactions with afferents are suggested to play a role in the development of synaptic circuits. Here, we show that the morphology of the axon terminal system and the dendritic field are selectively regulated by innervation from their respective afferents: genetic respecification of all cones to become rods, in Crxp-Nrl transgenic mice, produces an atrophic dendritic field yet leaves the axon terminal system largely intact. In contrast, in the retinas of Nrl-/- mice, in which the population of rod photoreceptors is respecified to adopt a cone fate, the dendritic field is hypertrophic, whereas the axon terminal system is underdeveloped. Our studies reveal that, although cell-intrinsic mechanisms drive the formation of independent dendritic versus axonal domains, the afferents play a selectively instructive role in defining their respective morphologies.