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:

Transmembrane semaphorin signalling controls laminar stratification in the mammalian retina

Nature volume 470, pages 259–263 (2011)Cite this article

This article has been updated

Abstract

In the vertebrate retina, establishment of precise synaptic connections among distinct retinal neuron cell types is critical for processing visual information and for accurate visual perception. Retinal ganglion cells (RGCs), amacrine cells and bipolar cells establish stereotypic neurite arborization patterns to form functional neural circuits in the inner plexiform layer (IPL)1,2,3, a laminar region that is conventionally divided into five major parallel sublaminae1,2. However, the molecular mechanisms governing distinct retinal subtype targeting to specific sublaminae within the IPL remain to be elucidated. Here we show that the transmembrane semaphorin Sema6A signals through its receptor PlexinA4 (PlexA4) to control lamina-specific neuronal stratification in the mouse retina. Expression analyses demonstrate that Sema6A and PlexA4 proteins are expressed in a complementary fashion in the developing retina: Sema6A in most ON sublaminae and PlexA4 in OFF sublaminae of the IPL. Mice with null mutations in PlexA4 or Sema6A exhibit severe defects in stereotypic lamina-specific neurite arborization of tyrosine hydroxylase (TH)-expressing dopaminergic amacrine cells, intrinsically photosensitive RGCs (ipRGCs) and calbindin-positive cells in the IPL. Sema6A and PlexA4 genetically interact in vivo for the regulation of dopaminergic amacrine cell laminar targeting. Therefore, neuronal targeting to subdivisions of the IPL in the mammalian retina is directed by repulsive transmembrane guidance cues present on neuronal processes.

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: PlexinA4 directs lamina-specific neurite arborization of dopaminergic amacrine cells and calbindin-positive cells in the IPL in vivo.
Figure 2: PlexinA4 controls dendritic targeting of M1-type ipRGCs within the IPL, but not co-localization of dopaminergic amacrine cell and ipRGC processes.
Figure 3: PlexinA4 and Sema6A exhibit complementary protein expression in the developing mouse retina.
Figure 4: Sema6A signalling through the PlexinA4 receptor directs retinal sublaminar targeting.

Similar content being viewed by others

Change history

  • 10 February 2011

    Three labels were corrected in Fig. 4.

References

  1. Wassle, H. Parallel processing in the mammalian retina. Nature Rev. Neurosci. 5, 747–757 (2004)

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Huberman, A. D., Clandinin, T. R. & Baier, H. Molecular and cellular mechanisms of lamina-specific axon targeting. Cold Spring Harb Perspect Biol 2, a001743 (2010)

    Article  Google Scholar 

  4. Yamagata, M., Weiner, J. A. & Sanes, J. R. Sidekicks: synaptic adhesion molecules that promote lamina-specific connectivity in the retina. Cell 110, 649–660 (2002)

    Article  CAS  Google Scholar 

  5. Yamagata, M. & Sanes, J. R. Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina. Nature 451, 465–469 (2008)

    Article  ADS  CAS  Google Scholar 

  6. 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 

  7. Fuerst, P. G., Harris, B. S., Johnson, K. R. & Burgess, R. W. A novel null allele of mouse DSCAM survives to adulthood on an inbred C3H background with reduced phenotypic variability. Genesis 48, 578–584 (2010)

    Article  CAS  Google Scholar 

  8. Tran, T. S., Kolodkin, A. L. & Bharadwaj, R. Semaphorin regulation of cellular morphology. Annu. Rev. Cell Dev. Biol. 23, 263–292 (2007)

    Article  CAS  Google Scholar 

  9. Leighton, P. A. et al. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature 410, 174–179 (2001)

    Article  ADS  CAS  Google Scholar 

  10. de Winter, F., Cui, Q., Symons, N., Verhaagen, J. & Harvey, A. R. Expression of class-3 semaphorins and their receptors in the neonatal and adult rat retina. Invest. Ophthalmol. Vis. Sci. 45, 4554–4562 (2004)

    Article  Google Scholar 

  11. Yaron, A., Huang, P. H., Cheng, H. J. & Tessier-Lavigne, M. Differential requirement for Plexin-A3 and -A4 in mediating responses of sensory and sympathetic neurons to distinct class 3 Semaphorins. Neuron 45, 513–523 (2005)

    Article  CAS  Google Scholar 

  12. Gu, C. et al. Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev. Cell 5, 45–57 (2003)

    Article  CAS  Google Scholar 

  13. Giger, R. J. et al. Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins. Neuron 25, 29–41 (2000)

    Article  CAS  Google Scholar 

  14. Famiglietti, E. V., Jr & Kolb, H. Structural basis for ON- and OFF-center responses in retinal ganglion cells. Science 194, 193–195 (1976)

    Article  ADS  Google Scholar 

  15. Viney, T. J. et al. Local retinal circuits of melanopsin-containing ganglion cells identified by transsynaptic viral tracing. Curr. Biol. 17, 981–988 (2007)

    Article  CAS  Google Scholar 

  16. Zhang, D. Q. et al. Intraretinal signaling by ganglion cell photoreceptors to dopaminergic amacrine neurons. Proc. Natl Acad. Sci. USA 105, 14181–14186 (2008)

    Article  ADS  CAS  Google Scholar 

  17. Hattar, S., Liao, H. W., Takao, M., Berson, D. M. & Yau, K. W. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295, 1065–1070 (2002)

    Article  ADS  CAS  Google Scholar 

  18. Pires, S. S. et al. Differential expression of two distinct functional isoforms of melanopsin (Opn4) in the mammalian retina. J. Neurosci. 29, 12332–12342 (2009)

    Article  CAS  Google Scholar 

  19. Suto, F. et al. Interactions between plexin-A2, plexin-A4, and semaphorin 6A control lamina-restricted projection of hippocampal mossy fibers. Neuron 53, 535–547 (2007)

    Article  CAS  Google Scholar 

  20. Stacy, R. C. & Wong, R. O. Developmental relationship between cholinergic amacrine cell processes and ganglion cell dendrites of the mouse retina. J. Comp. Neurol. 456, 154–166 (2003)

    Article  Google Scholar 

  21. Kay, J. N. et al. Transient requirement for ganglion cells during assembly of retinal synaptic layers. Development 131, 1331–1342 (2004)

    Article  CAS  Google Scholar 

  22. Runker, A. E., Little, G. E., Suto, F., Fujisawa, H. & Mitchell, K. J. Semaphorin-6A controls guidance of corticospinal tract axons at multiple choice points. Neural Develop. 3, 34 (2008)

    Article  Google Scholar 

  23. Kerjan, G. et al. The transmembrane semaphorin Sema6A controls cerebellar granule cell migration. Nature Neurosci. 8, 1516–1524 (2005)

    Article  CAS  Google Scholar 

  24. Yoshida, Y., Han, B., Mendelsohn, M. & Jessell, T. M. PlexinA1 signaling directs the segregation of proprioceptive sensory axons in the developing spinal cord. Neuron 52, 775–788 (2006)

    Article  CAS  Google Scholar 

  25. Cheng, H. J. et al. Plexin-A3 mediates semaphorin signaling and regulates the development of hippocampal axonal projections. Neuron 32, 249–263 (2001)

    Article  CAS  Google Scholar 

  26. Friedel, R. H. et al. Plexin-B2 controls the development of cerebellar granule cells. J. Neurosci. 27, 3921–3932 (2007)

    Article  CAS  Google Scholar 

  27. Pasterkamp, R. J., Peschon, J. J., Spriggs, M. K. & Kolodkin, A. L. Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 424, 398–405 (2003)

    Article  ADS  Google Scholar 

  28. Suto, F. et al. Plexin-a4 mediates axon-repulsive activities of both secreted and transmembrane semaphorins and plays roles in nerve fiber guidance. J. Neurosci. 25, 3628–3637 (2005)

    Article  CAS  Google Scholar 

  29. 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 

  30. 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 

Download references

Acknowledgements

We thank K.-W. Yau for the C-terminal melanopsin antibody, F. Suto for the PlexA4 antibody, B. Howell for the Dab-1 antibody, Y. Yoshida for the PlexA1−/− eyes, P. Mombaerts for the PlexB1−/− and PlexB3−/− mice (unpublished), C. Gu for the PlexD1-/flox ;nestin cre (unpublished) eyes and M. Tessier-Lavigne for the PlexA4−/− mice. We also thank J. Nathans, S. Hattar, K. Mandai and M. Riccomagno for comments on the manuscript and discussions, and members of the Kolodkin laboratory for assistance. This work was supported by R01 NS35165 to A.L.K., a predoctoral fellowship from the Nakajima Foundation to R.L.M., the Fondation pour la Recherche Médicale (Programme équipe FRM) to A.C., the Fondation Retina France to K.T.N.-B.-C., and a PhD fellowship from the Paris School of Neuroscience (ENP) to A.P. A.L.K. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Tudor C. Badea

    Present address: Present address: Retinal Circuit Development & Genetics Unit, Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, Maryland 20892, USA .,

Authors and Affiliations

  1. The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Ryota L. Matsuoka & Alex L. Kolodkin

  2. Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Tudor C. Badea

  3. Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Ryota L. Matsuoka, Tudor C. Badea & Alex L. Kolodkin

  4. Institut National de la Santé et de la Recherche Médicale (INSERM), UMR S968, Institut de la Vision, F-75012 Paris, France ,

    Kim T. Nguyen-Ba-Charvet, Aijaz Parray & Alain Chédotal

  5. Université Pierre et Marie Curie (UPMC) Paris VI, UMR S968, Institut de la Vision, F-75012 Paris, France ,

    Kim T. Nguyen-Ba-Charvet, Aijaz Parray & Alain Chédotal

  6. Centre National de la Recherche Scientifique (CNRS) UMR 7210, Institut de la Vision, F-75012 Paris, France ,

    Kim T. Nguyen-Ba-Charvet, Aijaz Parray & Alain Chédotal

Authors
  1. Ryota L. Matsuoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kim T. Nguyen-Ba-Charvet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aijaz Parray
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tudor C. Badea
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alain Chédotal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alex L. Kolodkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.L.M., A.C. and A.L.K. conceived and designed the experiments; R.L.M. performed most of the experiments and data analysis; K.T.N.-B.-C., A.P. and A.C. participated in the phenotypic analyses of Sema6A mutant mice and provided PlexA2−/− and PlexB2−/− mutants; T.C.B. performed cholera toxin injections and provided suggestions and reagents; R.L.M. and A.L.K. wrote the paper.

Corresponding author

Correspondence to Alex L. Kolodkin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-13 with legends and Supplementary References. (PDF 14489 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matsuoka, R., Nguyen-Ba-Charvet, K., Parray, A. et al. Transmembrane semaphorin signalling controls laminar stratification in the mammalian retina. Nature 470, 259–263 (2011). https://doi.org/10.1038/nature09675

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09675

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