Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 483, pages 465–469 (2012)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

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.

References

  1. Cook, J. E. & Chalupa, L. M. Retinal mosaics: new insights into an old concept. Trends Neurosci. 23, 26–34 (2000)

    Article  CAS  Google Scholar 

  2. Wässle, H. & Riemann, H. J. The mosaic of nerve cells in the mammalian retina. Proc. R. Soc. Lond. B 200, 441–461 (1978)

    Article  ADS  Google Scholar 

  3. Eglen, S. J. Development of regular cellular spacing in the retina: theoretical models. Math. Med. Biol. 23, 79–99 (2006)

    Article  Google Scholar 

  4. Reese, B. E. & Galli-Resta, L. The role of tangential dispersion in retinal mosaic formation. Prog. Retin. Eye Res. 21, 153–168 (2002)

    Article  Google Scholar 

  5. Rockhill, R. L., Euler, T. & Masland, R. H. Spatial order within but not between types of retinal neurons. Proc. Natl Acad. Sci. USA 97, 2303–2307 (2000)

    Article  ADS  CAS  Google Scholar 

  6. Huckfeldt, R. M. et al. Transient neurites of retinal horizontal cells exhibit columnar tiling via homotypic interactions. Nature Neurosci. 12, 35–43 (2009)

    Article  CAS  Google Scholar 

  7. Poché, R. A. et al. Somal positioning and dendritic growth of horizontal cells are regulated by interactions with homotypic neighbors. Eur. J. Neurosci. 27, 1607–1614 (2008)

    Article  Google Scholar 

  8. Galli-Resta, L. Local, possibly contact-mediated signalling restricted to homotypic neurons controls the regular spacing of cells within the cholinergic arrays in the developing rodent retina. Development 127, 1509–1516 (2000)

    CAS  PubMed  Google Scholar 

  9. Galli-Resta, L., Resta, G., Tan, S. S. & Reese, B. E. Mosaics of islet-1-expressing amacrine cells assembled by short-range cellular interactions. J. Neurosci. 17, 7831–7838 (1997)

    Article  CAS  Google Scholar 

  10. Wu, H.-H. et al. Glial precursors clear sensory neuron corpses during development via Jedi-1, an engulfment receptor. Nature Neurosci. 12, 1534–1541 (2009)

    Article  CAS  Google Scholar 

  11. MacDonald, J. M. et al. The Drosophila cell corpse engulfment receptor Draper mediates glial clearance of severed axons. Neuron 50, 869–881 (2006)

    Article  CAS  Google Scholar 

  12. Reddien, P. W. & Horvitz, H. R. The engulfment process of programmed cell death in Caenorhabditis elegans. Annu. Rev. Cell Dev. Biol. 20, 193–221 (2004)

    Article  CAS  Google Scholar 

  13. Hamon, Y. et al. Cooperation between engulfment receptors: the case of ABCA1 and MEGF10. PLoS ONE 1, e120 (2006)

    Article  ADS  Google Scholar 

  14. Suzuki, E. & Nakayama, M. MEGF10 is a mammalian ortholog of CED-1 that interacts with clathrin assembly protein complex 2 medium chain and induces large vacuole formation. Exp. Cell Res. 313, 3729–3742 (2007)

    Article  CAS  Google Scholar 

  15. Sanes, J. R. & Zipursky, S. L. Design principles of insect and vertebrate visual systems. Neuron 66, 15–36 (2010)

    Article  CAS  Google Scholar 

  16. Kay, J. N. et al. Retinal ganglion cells with distinct directional preferences differ in molecular identity, structure, and central projections. J. Neurosci. 31, 7753–7762 (2011)

    Article  CAS  Google Scholar 

  17. Kay, J. N., Voinescu, P. E., Chu, M. W. & Sanes, J. R. Neurod6 expression defines new retinal amacrine cell subtypes and regulates their fate. Nature Neurosci. 14, 965–972 (2011)

    Article  CAS  Google Scholar 

  18. Demb, J. B. Cellular mechanisms for direction selectivity in the retina. Neuron 55, 179–186 (2007)

    Article  CAS  Google Scholar 

  19. Haverkamp, S. & Wässle, H. Immunocytochemical analysis of the mouse retina. J. Comp. Neurol. 424, 1–23 (2000)

    Article  CAS  Google Scholar 

  20. Keeley, P. W., Whitney, I. E., Raven, M. A. & Reese, B. E. Dendritic spread and functional coverage of starburst amacrine cells. J. Comp. Neurol. 505, 539–546 (2007)

    Article  Google Scholar 

  21. Elshatory, Y. et al. Islet-1 controls the differentiation of retinal bipolar and cholinergic amacrine cells. J. Neurosci. 27, 12707–12720 (2007)

    Article  CAS  Google Scholar 

  22. Cahoy, J. D. et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008)

    Article  CAS  Google Scholar 

  23. Rodieck, R. W. The density recovery profile: a method for the analysis of points in the plane applicable to retinal studies. Vis. Neurosci. 6, 95–111 (1991)

    Article  CAS  Google Scholar 

  24. Raven, M. A., Eglen, S. J., Ohab, J. J. & Reese, B. E. Determinants of the exclusion zone in dopaminergic amacrine cell mosaics. J. Comp. Neurol. 461, 123–136 (2003)

    Article  Google Scholar 

  25. Fuerst, P. G., Koizumi, A., Masland, R. H. & Burgess, R. W. Neurite arborization and mosaic spacing in the mouse retina require DSCAM. Nature 451, 470–474 (2008)

    Article  ADS  CAS  Google Scholar 

  26. Fuerst, P. G. et al. DSCAM and DSCAML1 function in self-avoidance in multiple cell types in the developing mouse retina. Neuron 64, 484–497 (2009)

    Article  CAS  Google Scholar 

  27. Matsuda, T. & Cepko, C. L. Electroporation and RNA interference in the rodent retina in vivo and in vitro. Proc. Natl Acad. Sci. USA 101, 16–22 (2004)

    Article  ADS  CAS  Google Scholar 

  28. Solecki, D. J., Model, L., Gaetz, J., Kapoor, T. M. & Hatten, M. E. Par6α signaling controls glial-guided neuronal migration. Nature Neurosci. 7, 1195–1203 (2004)

    Article  CAS  Google Scholar 

  29. Budry, L. et al. Related pituitary cell lineages develop into interdigitated 3D cell networks. Proc. Natl Acad. Sci. USA 108, 12515–12520 (2011)

    Article  ADS  CAS  Google Scholar 

  30. Skarnes, W. C. et al. A conditional knockout resource for the genome-wide study of mouse gene function. Nature 474, 337–342 (2011)

    Article  CAS  Google Scholar 

  31. Huberman, A. D. et al. Genetic identification of an On-Off direction-selective retinal ganglion cell subtype reveals a layer-specific subcortical map of posterior motion. Neuron 62, 327–334 (2009)

    Article  CAS  Google Scholar 

  32. Gray, G. E. & Sanes, J. R. Lineage of radial glia in the chicken optic tectum. Development 114, 271–283 (1992)

    CAS  PubMed  Google Scholar 

  33. Hong, Y. K., Kim, I.-J. & Sanes, J. R. Stereotyped axonal arbors of retinal ganglion cell subsets in the mouse superior colliculus. J. Comp. Neurol. 519, 1691–1711 (2011)

    Article  CAS  Google Scholar 

  34. Euler, T. WinDRP website. http://www.mpimf-heidelberg.mpg.de/∼teuler/WinDRP/ReadMe.htm (2003)

  35. Whitney, I. E., Keeley, P. W., Raven, M. A. & Reese, B. E. Spatial patterning of cholinergic amacrine cells in the mouse retina. J. Comp. Neurol. 508, 1–12 (2008)

    Article  Google Scholar 

  36. Wiegand, T. & Moloney, K. A. Rings, circles, and null-models for point pattern analysis in ecology. Oikos 104, 209–229 (2004)

    Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Center for Brain Science and Department of Molecular and Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, Massachusetts 02138, USA,

    Jeremy N. Kay, Monica W. Chu & Joshua R. Sanes

Authors
  1. Jeremy N. Kay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monica W. Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joshua R. Sanes
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

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

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10877

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing