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.

Müller glia are a potential source of neural regeneration in the postnatal chicken retina

Abstract

The retina of warm-blooded vertebrates is believed to be incapable of neural regeneration. Here we provide evidence that the retina of postnatal chickens has the potential to generate new neurons. In response to acute damage, numerous Müller glia re-entered the cell cycle, and shortly thereafter, expressed CASH-1, Pax6 and Chx10, transcription factors expressed by embryonic retinal progenitors. These progenitor-like cells transiently expressed neurofilament. Newly formed cells became distributed throughout the inner and outer nuclear layers of the retina, and remained for at least three weeks after damage. Some of these newly formed cells differentiated into retinal neurons, a few formed Müller glia, and most remained undifferentiated, with continued expression of Pax6 and Chx10. These cells continued to proliferate when grown in culture, with some differentiating into retinal neurons or Müller glia. We propose that, in response to damage, Müller glia in the retina are a potential source of neural regeneration.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Acute damage causes many cells in the chick retina to proliferate.
Figure 2: BrdU accumulates in microglia that express a lysosomal glycoprotein and Müller glia that express glutamine synthetase after acute damage.
Figure 3: The number of BrdU-labeled cells in toxin-damaged retina that are immunoreactive for glutamine synthetase decreases with increasing time after toxin treatment.
Figure 4: Many progenitor-like cells accumulate in the retina after acute damage.
Figure 5: Neurofilament-like protein is transiently expressed by proliferating Müller glia in toxin-damaged retina.
Figure 6: New neurons are generated in the chicken retina after acute damage.
Figure 7: Neurons and glia are produced by damage-induced progenitor-like cells in vitro.

Similar content being viewed by others

References

  1. Raymond, P. A. & Hitchcock, P. F. Retinal regeneneration: common principles but diversity of mechanisms. Adv. Neurol. 72, 171–184 (1997).

    CAS  PubMed  Google Scholar 

  2. Reh, T. A. & Levine, E. M. Multipotential stem cells and progenitors in the vertebrate retina. J. Neurobiol. 80, 206–220 (1988).

    Google Scholar 

  3. Johns, P. R. & Fernald, R. D. Genesis of rods in teleost fish retina. Nature 293, 141–142 (1981).

    Article  CAS  Google Scholar 

  4. Johns, P. R. Formation of photoreceptors in larval and adult goldfish. J. Neurosci. 176, 343–357 (1982).

    Google Scholar 

  5. Goldman, S. A. & Nottebohm, F. Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain. Proc. Natl. Acad. Sci. USA 80, 2390–2394 (1983).

    Article  CAS  Google Scholar 

  6. Fischer, A. J. & Reh, T. A. Identification of a proliferating marginal zone of retinal progenitors in postnatal chickens. Dev. Biol. 220, 197–210 (2000).

    Article  CAS  Google Scholar 

  7. Reynolds, B. A. & Weiss, S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255, 1707–1710 (1992).

    Article  CAS  Google Scholar 

  8. Tropepe, V. et al. Retinal stem cells in the adult mouse eye. Science 287, 2032–2036 (2000).

    Article  CAS  Google Scholar 

  9. Scharff, C., Kirn, J. R., Grossman, M., Macklis, J. D. & Nottenbohm, F. Targeted neuronal death affects replacement and vocal behavior in adult songbirds. Neuron 25, 481–492 (2000).

    Article  CAS  Google Scholar 

  10. Magavi, S. S., Leavitt, B. R. & Macklis, J. D. Induction of neurogenesis in the neocortex of adult mice. Nature 405, 951–955 (2000).

    Article  CAS  Google Scholar 

  11. Coulombre, J. L. & Coulombre, A. J. Regeneration of neural retina from pigmented epithelium in the chick embryo. Dev. Biol. 12, 79–92 (1965).

    Article  CAS  Google Scholar 

  12. Park, C. M. & Hollenberg, M. J. Basic fibroblast growth factor induces retinal regeneration in vivo. Dev. Biol. 134, 201–205 (1989).

    Article  CAS  Google Scholar 

  13. Willbold, E. & Layer, P. G. A hidden retina regenerative capacity from the chick ciliary margin is reactivated in vitro, that is accompanied by down-regulation of butyrylcholinesterase. Eur. J. Neurosci. 4, 210–220 (1991).

    Article  Google Scholar 

  14. Reh, T.A. & Pittack, C. Transdifferentiation and retinal regeneration. Semin. Cell Biol. 6, 137–142 (1995).

    Article  CAS  Google Scholar 

  15. Prada, C., Puga, J., Pérez-Méndez, L., Lóper, R. & Ramírez, G. Spatial and temporal patterns of neurogenesis in the chick retina. Eur. J. Neurosci. 3, 559–569 (1991).

    Article  Google Scholar 

  16. Gould, E. & Tanapat, B. S. Lesion-induced proliferation of neuronal progenitors in the dentate gyrus of the adult rat. Neuroscience 80, 427–436 (1997).

    Article  CAS  Google Scholar 

  17. Reh, T. A. Cell-specific regulation of neuronal production in the larval frog retina. J. Neurosci. 7, 3317–3324 (1987).

    Article  CAS  Google Scholar 

  18. Barrington, M. J., Sattayasai, J., Zappia, J. & Ehrlich . Excitatory amino acids interfere with normal eye growth in posthatch chicks. Curr. Eye Res. 8, 781–792 (1989).

    Article  CAS  Google Scholar 

  19. Ehrlich, D., Sattayasai, J., Zappia, J. & Barrington, M. in Myopia and the Control of Eye Growth—Symposium No. 155 (eds. Bock, G. R. & Widdows, K.) 63–84 (John Wiley & Sons, Chichester, England, 1990).

    Google Scholar 

  20. Tung, N. N., Morgan, I. G. & Ehrlich, D. A quantitative analysis of the effects of excitatory neurotoxins on retinal ganglion cells in the chick. Vis. Neurosci. 4, 217–223 (1990).

    Article  CAS  Google Scholar 

  21. Fischer, A. J., Seltner, R. L. P., Poon, J. & Stell, W. K. Immunocytochemical characterization of NMDA and QA-induced excitotoxicity in the retina of chicks. J. Comp. Neurol. 393, 1–15 (1998).

    Article  CAS  Google Scholar 

  22. Chadee, D. N. et al. Increased phosphorylation of histone H1 in mouse fibroblasts transformed with oncogenes or constitutively active mitogen-activated protein kinase kinase. J. Biol. Chem. 270, 20098–20105 (1995).

    Article  CAS  Google Scholar 

  23. Mahadevan, L. C., Willis, A. C. & Baratt, M. S. Rapid histone H3 phosphorylation in response to growth factors, phorbol esters, okadaic acid, and protein synthesis inhibitors. Cell 65, 775–783 (1991).

    Article  CAS  Google Scholar 

  24. Ajiro, K., Yoda, K., Utsumi, K. & Nishikawa, Y. Alteration of cell cycle-dependent histone phosphorylations by okadaic acid. Induction of mitosis-specific H3 phosphorylation and chromatin condensation in mammalian interphase cells. J. Biol. Chem. 271, 13197–13207 (1996).

    Article  CAS  Google Scholar 

  25. Belecky-Adams, T. et al. Pax-6, Prox 1, and Chx10 homeobox gene expression correlates with phenotypic fate of retinal precursor cells. Invest. Ophthal. Vis. Sci. 38, 1293–1303 (1997).

    CAS  PubMed  Google Scholar 

  26. Jasoni, C. L., Walker, M. B., Morrism M. D. & Reh T. A. A chicken acheate-scute homolog (CASH-1) is expressed in a temporally and spatially discrete manner in the developing nervous system. Development 120, 769–783 (1994).

    CAS  PubMed  Google Scholar 

  27. Fischer, A. J., Wallman, J., Mertz, J. & Stell, W. K. Localization of retinoid binding proteins, receptors, and synthetic enzymes to the ocular tissues of the chick. J. Neurocytol. 58, 697–609 (1999).

    Google Scholar 

  28. Braisted, J. E., Essman, T. F. & Raymond, P. A. Selective regeneration of photoreceptors in goldfish retina. Development 122, 1427–1438 (1994).

    Google Scholar 

  29. Negishi, K. et al. Induction of immunoreactive proliferating cell nuclear antigen (PCNA) in goldfish retina following intravitreal injection with tunicamycin. Brain Res. Dev. Brain Res. 63, 71–83 (1991).

    Article  CAS  Google Scholar 

  30. Oesterie, E. C. & Rubel, E. W. Hair cell generation in vestibular sensory receptor epithelia. Ann. NY Acad. Sci. 78, 34–46 (1996).

    Article  Google Scholar 

  31. Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 11, 703–716 (1999).

    Article  Google Scholar 

  32. Tomita, K., Nakanishi, S., Guillemot, F. & Kageyama, R. Mash1 promotes neuronal differentiation in the retina. Genes Cells 1, 765–774 (1996).

    Article  CAS  Google Scholar 

  33. Takahashi, M., Palmer, T. D., Takahashi, J. & Gage, F. H. Widespread integration and survival of adult-derived neural progenitor cells in the developing optic retina. Mol. Cell. Neurosci. 12, 340–348 (1998).

    Article  CAS  Google Scholar 

  34. Anchan, R. M., Reh, T. A., Angello, J., Balliet, A. & Walker, M. EGF and TGF-α stimulate retinal neuroepithelial cell proliferation in vitro. Neuron 6, 923–936 (1991).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank B. Dierks for technical assistance, and W.K. Stell, D. Raible and J. Hurley for comments on the manuscript. The BrdU, Pax6, vimentin, neurofilament and LEP-100 antibodies developed by S.J. Kaufman, A. Kawakami, J. Sanes, J. Wood and D.M. Fambrough, respectively, were obtained from the DSHB developed under auspices of the NICHD and maintained by the University of Iowa, Department of Biological Sciences, Iowa City, Iowa 52242. This work was supported by fellowships to A.J.F from the Alberta Heritage Foundation for Medical Research, the Medical Research Council of Canada, and the Fight for Sight Foundation Research Division of Prevent Blindness America, and by grants to T.A.R. from the National Science Foundation, NSF9604843 the Foundation Fighting Blindness and NIH NS28308.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thomas A. Reh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fischer, A., Reh, T. Müller glia are a potential source of neural regeneration in the postnatal chicken retina. Nat Neurosci 4, 247–252 (2001). https://doi.org/10.1038/85090

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/85090

This article is cited by

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