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Ephrin-As and neural activity are required for eye-specific patterning during retinogeniculate mapping

Nature Neuroscience volume 8, pages 1022–1027 (2005)Cite this article

Abstract

In mammals, retinal ganglion cell (RGC) projections initially intermingle and then segregate into a stereotyped pattern of eye-specific layers in the dorsal lateral geniculate nucleus (dLGN). Here we found that in mice deficient for ephrin-A2, ephrin-A3 and ephrin-A5, eye-specific inputs segregated but the shape and location of eye-specific layers were profoundly disrupted. In contrast, mice that lacked correlated retinal activity did not segregate eye-specific inputs. Inhibition of correlated neural activity in ephrin mutants led to overlapping retinal projections that were located in inappropriate regions of the dLGN. Thus, ephrin-As and neural activity act together to control patterning of eye-specific retinogeniculate layers.

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Figure 1: Expression of EphA receptors and ephrin-A ligands in the developing mouse visual system.
Figure 2: Defects in eye-specific layer placement but not in eye-specific segregation in ephrin-A2/A3/A5 triple-mutant mice.
Figure 3: Time course of eye-specific segregation in wild-type and ephrin-A2/A3/A5 triple-mutant mice.
Figure 4: Area of dLGN overlap is increased in epibatidine-treated ephrin-A2/A3/A5 triple-mutant mice as compared with epibatidine-treated wild-type mice.
Figure 5: Spontaneous retinal waves in ephrin-A2/A3/A5 triple-mutant retinas.

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References

  1. Feldheim, D.A. et al. Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping. Neuron 25, 563–574 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Feldheim, D.A. et al. Topographic guidance labels in a sensory projection to the forebrain. Neuron 21, 1303–1313 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Feldheim, D.A. et al. Loss-of-function analysis of EphA receptors in retinotectal mapping. J. Neurosci. 24, 2542–2550 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vanderhaeghen, P. & Polleux, F. Developmental mechanisms patterning thalamocortical projections: intrinsic, extrinsic and in between. Trends Neurosci. 27, 384–391 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. McLaughlin, T., Hindges, R. & O'Leary, D.D. Regulation of axial patterning of the retina and its topographic mapping in the brain. Curr. Opin. Neurobiol. 13, 57–69 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Metin, C., Godement, P., Saillour, P. & Imbert, M. [Physiological and anatomical study of the retinogeniculate projections in the mouse.] C. R. Seances Acad. Sci. III 296, 157–162 (1983).

    CAS  PubMed  Google Scholar 

  7. Rossi, F.M. et al. Requirement of the nicotinic acetylcholine receptor beta 2 subunit for the anatomical and functional development of the visual system. Proc. Natl. Acad. Sci. USA 98, 6453–6458 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sretavan, D.W., Shatz, C.J. & Stryker, M.P. Modification of retinal ganglion cell axon morphology by prenatal infusion of tetrodotoxin. Nature 336, 468–471 (1988).

    Article  CAS  PubMed  Google Scholar 

  9. Shatz, C.J. & Stryker, M.P. Prenatal tetrodotoxin infusion blocks segregation of retinogeniculate afferents. Science 242, 87–89 (1988).

    Article  CAS  PubMed  Google Scholar 

  10. Penn, A.A., Riquelme, P.A., Feller, M.B. & Shatz, C.J. Competition in retinogeniculate patterning driven by spontaneous activity. Science 279, 2108–2112 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Sretavan, D.W. & Shatz, C.J. Prenatal development of retinal ganglion cell axons: segregation into eye-specific layers within the cat's lateral geniculate nucleus. J. Neurosci. 6, 234–251 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rakic, P. Development of visual centers in the primate brain depends on binocular competition before birth. Science 214, 928–931 (1981).

    Article  CAS  PubMed  Google Scholar 

  13. Godement, P., Salaun, J. & Metin, C. Fate of uncrossed retinal projections following early or late prenatal monocular enucleation in the mouse. J. Comp. Neurol. 255, 97–109 (1987).

    Article  CAS  PubMed  Google Scholar 

  14. Stellwagen, D. & Shatz, C.J. An instructive role for retinal waves in the development of retinogeniculate connectivity. Neuron 33, 357–367 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Crowley, J.C. & Katz, L.C. Ocular dominance development revisited. Curr. Opin. Neurobiol. 12, 104–109 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Huberman, A.D. et al. Eye-specific retinogeniculate segregation independent of normal neuronal activity. Science 300, 994–998 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Muir-Robinson, G., Hwang, B.J. & Feller, M.B. Retinogeniculate axons undergo eye-specific segregation in the absence of eye-specific layers. J. Neurosci. 22, 5259–5264 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huberman, A.D., Stellwagen, D. & Chapman, B. Decoupling eye-specific segregation from lamination in the lateral geniculate nucleus. J. Neurosci. 22, 9419–9429 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shatz. Emergence of order in visual system development. Proc. Natl. Acad. Sci. USA 93, 602–608 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Crowley, J.C. & Katz, L.C. Development of ocular dominance columns in the absence of retinal input. Nat. Neurosci. 2, 1125–1130 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Chapman, B. Necessity for afferent activity to maintain eye-specific segregation in ferret lateral geniculate nucleus. Science 287, 2479–2482 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Frisén, J. et al. Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system. Neuron 20, 235–243 (1998).

    Article  PubMed  Google Scholar 

  23. Cutforth, T. et al. Axonal ephrin-As and odorant receptors: coordinate determination of the olfactory sensory map. Cell 114, 311–322 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Flanagan, J.G. & Vanderhaeghen, P. The ephrins and Eph receptors in neural development. Annu. Rev. Neurosci. 21, 309–345 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Grubb, M.S., Rossi, F.M., Changeux, J.P. & Thompson, I.D. Abnormal functional organization in the dorsal lateral geniculate nucleus of mice lacking the beta 2 subunit of the nicotinic acetylcholine receptor. Neuron 40, 1161–1172 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Adams, D.L. & Horton, J.C. Capricious expression of cortical columns in the primate brain. Nat. Neurosci. 6, 113–114 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Williams, S.E. et al. Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm. Neuron 39, 919–935 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Pham, T.A., Rubenstein, J.L., Silva, A.J., Storm, D.R. & Stryker, M.P. The CRE/CREB pathway is transiently expressed in thalamic circuit development and contributes to refinement of retinogeniculate axons. Neuron 31, 409–420 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Huh, G.S. et al. Functional requirement for class I MHC in CNS development and plasticity. Science 290, 2155–2159 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hanson, M.G. & Landmesser, L.T. Normal patterns of spontaneous activity are required for correct motor axon guidance and the expression of specific guidance molecules. Neuron 43, 687–701 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Demas, J., Eglen, S.J. & Wong, R.O. Developmental loss of synchronous spontaneous activity in the mouse retina is independent of visual experience. J. Neurosci. 23, 2851–2860 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huberman, A.D., Murray, K.D., Warland, D.K., Feldheim, D.A. & Chapman, B. Ephrin-As mediate targeting of eye-specific projections to the lateral geniculate nucleus. Nat. Neurosci. 8, 1011–1019 (2005).

    Article  Google Scholar 

  33. Flanagan, J.G. In situ analysis of embryos with receptor or ligand fusion protein probes. Curr. Biol. 10, R52–R53 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Tian, N. & Copenhagen, D.R. Visual stimulation is required for refinement of ON and OFF pathways in postnatal retina. Neuron 39, 85–96 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Wong, R.O.L., Meister, M. & Shatz, C.J. Transient period of correlated bursting activity during development of the mammalian retina. Neuron 11, 923–938 (1993).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank B. Chapman and A. Huberman for discussions and sharing data prior to publication. We thank C. Chen, P. Vanderhaeghen and C. Mason for discussions and critical reading of the manuscript and R. Axel for support (T.C.). This work was supported by a US National Institutes of Health (NIH) grant EY014689 (D.A.F.), an NIH predoctoral training grant GM08646 (C.P.) and NIH grants R01 DC04209 and P01 CA23767 (T.C.).

Author information

Authors and Affiliations

  1. Department of Molecular, Cellular, and Developmental Biology, University of California at Santa Cruz, Santa Cruz, 95064, California, USA

    Cory Pfeiffenberger, Georgia Woods, Jena Yamada & David A Feldheim

  2. Center for Neurobiology and Behavior, Columbia University Medical Center, New York, 10032, New York, USA

    Tyler Cutforth

  3. Department of Ophthalmology and Department of Physiology, University of California School of Medicine, San Francisco, San Francisco, 94143, California, USA

    René C Rentería & David R Copenhagen

  4. Department of Cell Biology and Program in Neuroscience, Harvard Medical School, Boston, 02115, Massachusetts, USA

    John G Flanagan

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Correspondence to David A Feldheim.

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Supplementary information

Supplementary Fig. 1

No qualitative difference in EphA receptor expression in the retina or dLGN at P6 after epibatidine injection into the eye. (PDF 4256 kb)

Supplementary Fig. 2

Stereotypical and bilaterally symmetric defects of ipsilateral projections to the dLGN in ephrin-A2/A3/A5 triply mutant mice. (PDF 2291 kb)

Supplementary Fig. 3

Normal optic chaism crossing in ephrin-A2/A3/A5 triple mutant mice. (PDF 1719 kb)

Supplementary Fig. 4

Two step mechanism for retinogeniculate map development. (PDF 1226 kb)

Supplementary Video 1

Movie of stacked 10μm confocal optical sections demonstrating the continuous ipsilateral layer in the wild-type adult dLGN. Axons from the ipsilateral eye are shown in green, axons from the contalateral eye are shown in red. The movie progresses from the most anterior section to the most posterior. Dorsal is to the top, lateral is to the right. (AVI 22276 kb)

Supplementary Video 2

Movie of stacked 10μm confocal optical sections demonstrating the continuous, yet branching structure of the ipsilateral layer in an ephrin-A2/A3/A5 triply mutant adult dLGN. Axons from the ipsilateral eye are shown in green, axons from the contralateral eye are shown in red. The movie progresses from the most anterior section to the most posterior. Dorsal is to the top, lateral is to the right. (AVI 40709 kb)

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Pfeiffenberger, C., Cutforth, T., Woods, G. et al. Ephrin-As and neural activity are required for eye-specific patterning during retinogeniculate mapping. Nat Neurosci 8, 1022–1027 (2005). https://doi.org/10.1038/nn1508

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