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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 neighbours of the same subtype than would occur by chance, resulting in ‘exclusion zones’ that separate them1,2,3,4. 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: although 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 neighbouring 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 interactions1,4,5,6,7,8,9. So far, however, no molecules have been identified that show such activity, so this hypothesis remains untested. Here we demonstrate in mouse that two related transmembrane proteins, MEGF10 and MEGF11, have critical roles in the formation of mosaics by two retinal interneuron subtypes, starburst amacrine cells and horizontal cells. MEGF10 and 11 and their invertebrate relatives Caenorhabditis elegans CED-1 and Drosophila Draper have hitherto been studied primarily as receptors necessary for engulfment of debris following apoptosis or axonal injury10,11,12,13,14. Our results demonstrate that members of this gene family can also serve as subtype-specific ligands that pattern neuronal arrays.

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Figure 1: Expression of Megf10 and Megf11 in SACs and HCs.
Figure 2: Loss of SAC mosaic spacing in Megf10 mutant mice.
Figure 3: HC mosaic spacing requires Megf10 and Megf11.
Figure 4: MEGF10 acts as both ligand and receptor to trigger SAC repulsion.

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Primary accessions

Gene Expression Omnibus

Data deposits

Data have been deposited at the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession code GSE35077.

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Acknowledgements

We thank B. Tilton, P. Rogers, J. Couget, and the Harvard Genome Modification Facility for technical assistance; S. Sarin and M. Yamagata for critical discussions; the National Institutes of Health (NS029169 and EY022073 to J.R.S.) and Life Sciences Research Foundation (J.N.K.) for funding.

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J.N.K. and J.R.S. designed experiments and wrote the paper. J.N.K. and M.W.C. performed experiments. J.N.K. performed data analysis. J.R.S. supervised the project.

Corresponding author

Correspondence to Joshua R. Sanes.

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The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Figures 1-12 and Supplementary Tables 1-4, which include additional notes and references. (PDF 4647 kb)

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Kay, J., Chu, M. & Sanes, J. MEGF10 and MEGF11 mediate homotypic interactions required for mosaic spacing of retinal neurons. Nature 483, 465–469 (2012). https://doi.org/10.1038/nature10877

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