MEGF10 and MEGF11 mediate homotypic interactions required for mosaic spacing of retinal neurons

Abstract

In many parts of the nervous system, neuronal somata display orderly spatial arrangements1. In the retina, neurons of numerous individual subtypes form regular arrays called mosaics: they are less likely to be near neighbors of the same subtype than would occur by chance, resulting in “exclusion zones” that separate them1-4. Mosaic arrangements provide a mechanism to distribute each cell type evenly across the retina, ensuring that all parts of the visual field have access to a full set of processing elements2. Remarkably, mosaics are independent of each other: while a neuron of one subtype is unlikely to be adjacent to another of the same subtype, there is no restriction on its spatial relationship to neighboring neurons of other subtypes5. This independence has led to the hypothesis that molecular cues expressed by specific subtypes pattern mosaics by mediating homotypic (within-subtype) short-range repulsive interactions1,4-9. To date, however, no molecules have been identified that show such activity, so this hypothesis remains untested. Here, we demonstrate that two related transmembrane proteins, MEGF10 and MEGF11, play critical roles in formation of mosaics by two retinal interneuron subtypes, starburst amacrine cells (SACs) and horizontal cells (HCs). MEGF10/11 and their invertebrate relatives C. elegans CED-1 and Drosophila Draper, have hitherto been studied primarily as receptors necessary for engulfment of debris following apoptosis or axonal injury10-14. Our results demonstrate that members of this gene family can also serve as subtype-specific ligands that pattern neuronal arrays.