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Control of Müller glial cell proliferation and activation following retinal injury

Abstract

Müller glial cells are the major support cell for neurons in the vertebrate retina. Following neuronal damage, Müller cells undergo reactive gliosis, which is characterized by proliferation and changes in gene expression. We have found that downregulation of the tumor supressor protein p27Kip1 and re-entry into the cell cycle occurs within the first 24 hours after retinal injury. Shortly thereafter, Müller glial cells upregulate genes typical of gliosis and then downregulate cyclin D3, in concert with an exit from mitosis. Mice lacking p27Kip1 showed a constitutive form of reactive gliosis, which leads to retinal dysplasia and vascular abnormalities reminiscent of diabetic retinopathy. We conclude that p27Kip1 regulates Müller glial cell proliferation during reactive gliosis.

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Figure 1: Expression of p27Kip1 and cyclin D3 in the adult mouse retina.
Figure 2: Changes in gene expression in Müller glial cells following retinal injury.
Figure 3: Characterization of Müller glial cells in the retinae of p27Kip1-deficient mice.
Figure 4: Characterization of the retinal dysplasia found in p27Kip1-deficient mice.
Figure 5: Induction of reactive gliosis during retinal development.
Figure 6: Examination of the vasculature in retinae undergoing reactive gliosis.

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References

  1. Ridet, J. L., Malhotra, S. K., Privat, A. & Gage, F. H. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20, 570–577 (1997). [erratum appears in Trends Neurosci. 21, 80, 1998]

    Article  CAS  Google Scholar 

  2. Wilson, J. X. Antioxidant defense of the brain: a role for astrocytes. Can. J. Physiol. Pharmacol. 75, 1149–1163 (1997).

    Article  CAS  Google Scholar 

  3. Ide, C. F. et al. Cellular and molecular correlates to plasticity during recovery from injury in the developing mammalian brain. Prog. Brain Res. 108, 365–377 (1996).

    Article  CAS  Google Scholar 

  4. Streit, W. J., Walter, S. A. & Pennell, N. A. Reactive microgliosis. Prog. Neurobiol. 57, 563–581 (1999).

    Article  CAS  Google Scholar 

  5. Unger, J. W. Glial reaction in aging and Alzheimer's disease. Microsc. Res. Tech. 43, 24–28 (1998).

    Article  CAS  Google Scholar 

  6. Streit, W. J. Microglial response to brain injury: a brief synopsis. Toxicol. Pathol. 28, 28–30 (2000).

    Article  CAS  Google Scholar 

  7. MacLaren, R. E. Development and role of retinal glia in regeneration of ganglion cells following retinal injury. Br. J. Ophthalmol. 80, 458 –464 (1996).

    Article  CAS  Google Scholar 

  8. Sahel, J. A., Albert, D. M. & Lessell, S. [Proliferation of retinal glia and excitatory amino acids]. Ophtalmologie 4, 13– 16 (1990).

    CAS  Google Scholar 

  9. Humphrey, M. F., Constable, I. J., Chu, Y. & Wiffen, S. A quantitative study of the lateral spread of Muller cell responses to retinal lesions in the rabbit. J. Comp. Neurol. 334, 545–558 (1993).

    Article  CAS  Google Scholar 

  10. Rutka, J. T. & Smith, S. L. Transfection of human astrocytoma cells with glial fibrillary acidic protein complementary DNA: analysis of expression, proliferation, and tumorigenicity. Cancer Res. 53, 3624–3631 (1993).

    CAS  Google Scholar 

  11. Reichenbach, A. et al. The Muller (glial) cell in normal and diseased retina: a case for single-cell electrophysiology. Ophthalmic Res. 29, 326–340 (1997).

    Article  CAS  Google Scholar 

  12. Sueishi, K. et al. Endothelial and glial cell interaction in diabetic retinopathy via the function of vascular endothelial growth factor (VEGF). Pol. J. Pharmacol. 48, 307–316 (1996).

    CAS  Google Scholar 

  13. Amin, R. H. et al. Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 38, 36–47 (1997).

    CAS  Google Scholar 

  14. Taomoto, M. et al. Retinal degeneration induced by N-methyl-N-nitrosourea in Syrian golden hamsters. Graefes Arch. Clin. Exp. Ophthalmol. 236, 688–695 (1998).

    Article  CAS  Google Scholar 

  15. Hjelmeland, L. E. & Harvey, A. K. in Progress in Retinal Research, Vol. 7 (eds. Osborn, N. & Chader, G. 259–281 (Pergamon, New York, 1988).

    Google Scholar 

  16. Nork, T. M., Ghobrial, M. W., Peyman, G. A. & Tso, M. O. Massive retinal gliosis. A reactive proliferation of Muller cells. Arch. Ophthalmol. 104, 1383–1389 (1986).

    Article  CAS  Google Scholar 

  17. Cogan, D. G. Congenital anomalies of the retina. Birth Defects Orig. Artic. Ser. 7, 41–51 (1971).

    CAS  Google Scholar 

  18. Berger, B., Peyman, G. A., Juarez, C., Mason, G. & Raichand, M. Massive retinal gliosis simulating choroidal melanoma. Can. J. Ophthalmol. 14, 285–290 (1979).

    CAS  Google Scholar 

  19. Dithmar, S., Holz, F. G. & Volcker, H. E. [Massive reactive gliosis of the retina.] Klin. Monatsbl. Augenheilkd 211, 338– 341 (1997).

    Article  CAS  Google Scholar 

  20. Elledge, S. J. Cell cycle checkpoints: preventing an identity crisis. Science 274, 1664–1672 (1996).

    Article  CAS  Google Scholar 

  21. Sherr, C. J. & Roberts, J. M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 9, 1149– 1163 (1995).

    Article  CAS  Google Scholar 

  22. Sanchez, I. & Dynlacht, B. D. Transcriptional control of the cell cycle. Curr. Opin. Cell Biol. 8, 318 –324 (1996).

    Article  CAS  Google Scholar 

  23. Yee, A. S., Shih, H. H. & Tevosian, S. G. New perspectives on retinoblastoma family functions in differentiation. Front. Biosci. 3, D532 –547 (1998).

    Article  CAS  Google Scholar 

  24. Hengst, L. & Reed, S. I. Inhibitors of the Cip/Kip family . Curr. Top. Microbiol. Immunol. 227, 25 –41 (1998).

    CAS  Google Scholar 

  25. Nakayama, K. et al. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85, 707–720 (1996).

    Article  CAS  Google Scholar 

  26. Dowling, J. E. The Retina—An Approachable Part of the Brain (Harvard Univ. Press, Cambridge, Massachusetts, 1987).

    Google Scholar 

  27. LaBaer, J. et al. New functional activities for the p21 family of CDK inhibitors . Genes Dev. 11, 847–862 (1997).

    Article  CAS  Google Scholar 

  28. Cheng, M. et al. The p21(Cip1) and p27(Kip1) CDK ‘inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J. 18, 1571–1583 (1999).

    Article  CAS  Google Scholar 

  29. Kiyokawa, H. et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell 85, 721–732 (1996).

    Article  CAS  Google Scholar 

  30. Fero, M. L. et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell 85, 733–744 (1996).

    Article  CAS  Google Scholar 

  31. Rich, K. A., Figueroa, S. L., Zhan, Y. & Blanks, J. C. Effects of Muller cell disruption on mouse photoreceptor cell development . Exp. Eye Res. 61, 235– 248 (1995).

    Article  CAS  Google Scholar 

  32. Cepko, C. L. et al. Lineage analysis using retroviral vectors. Methods 14, 393–406 (1998).

    Article  CAS  Google Scholar 

  33. Turner, D. L. & Cepko, C. L. A common progenitor for neurons and glia persists in rat retina late in development. Nature 328, 131–136 (1987).

    Article  CAS  Google Scholar 

  34. Fields-Berry, S. C., Halliday, A. L. & Cepko, C. L. A recombinant retrovirus encoding alkaline phosphatase confirms clonal boundary assignment in lineage analysis of murine retina. Proc. Natl. Acad. Sci. USA 89, 693– 697 (1992).

    Article  CAS  Google Scholar 

  35. Nork, T. M., Wallow, I. H., Sramek, S. J. & Anderson, G. Muller's cell involvement in proliferative diabetic retinopathy. Arch. Ophthalmol. 105, 1424–1429 (1987).

    Article  CAS  Google Scholar 

  36. Robison, W. G. Jr., Tillis, T. N., Laver, N. & Kinoshita, J. H. Diabetes-related histopathologies of the rat retina prevented with an aldose reductase inhibitor. Exp. Eye Res. 50, 355–366 (1990).

    Article  CAS  Google Scholar 

  37. Fariss, R. N., Li, Z. Y. & Milam, A. H. Abnormalities in rod photoreceptors, amacrine cells, and horizontal cells in human retinas with retinitis pigmentosa. Am. J. Ophthalmol. 129, 215–223 (2000).

    Article  CAS  Google Scholar 

  38. Li, Z. Y., Possin, D. E. & Milam, A. H. Histopathology of bone spicule pigmentation in retinitis pigmentosa. Ophthalmology 102, 805– 816 (1995).

    Article  CAS  Google Scholar 

  39. Kimura, H. et al. Cellular response in subretinal neovascularization induced by bFGF-impregnated microspheres. Invest. Ophthalmol. Vis. Sci. 40, 524–528 (1999).

    CAS  Google Scholar 

  40. Kuhrt, H. et al. Changes in CD44 and ApoE immunoreactivities due to retinal pathology of man and rat. J. Hirnforsch. 38, 223– 229 (1997).

    CAS  Google Scholar 

  41. Birnbach, C. D., Jarvelainen, M., Possin, D. E. & Milam, A. H. Histopathology and immunocytochemistry of the neurosensory retina in fundus flavimaculatus. Ophthalmology 101, 1211– 1219 (1994).

    Article  CAS  Google Scholar 

  42. Madigan, M. C., Penfold, P. L., Provis, J. M., Balind, T. K. & Billson, F. A. Intermediate filament expression in human retinal macroglia. Histopathologic changes associated with age-related macular degeneration. Retina 14, 65– 74 (1994).

    Article  CAS  Google Scholar 

  43. Foisner, R. Dynamic organisation of intermediate filaments and associated proteins during the cell cycle. Bioessays 19, 297– 305 (1997).

    Article  CAS  Google Scholar 

  44. Levine, E. M., Close, J., Fero, M., Ostrovsky, A. & Reh, T. A. p27(Kip1) regulates cell cycle withdrawal of late multipotent progenitor cells in the mammalian retina. Dev. Biol. 219, 299–314 (2000).

    Article  CAS  Google Scholar 

  45. Matsuoka, S. et al. p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev. 9, 650–662 (1995).

    Article  CAS  Google Scholar 

  46. Dyer, M. A. & Cepko, C. L. p57 regulates progenitor cell proliferation and amacrine interneuron development in the mouse retina. Development (in press).

  47. Morrow, E. M., Belliveau, M. J. & Cepko, C. L. Two phases of rod photoreceptor differentiation during rat retinal development. J. Neurosci. 18, 3738–3748 (1998).

    Article  CAS  Google Scholar 

  48. Cepko, C. L., Fields-Berry, S., Ryder, E., Austin, C. & Golden, J. Lineage analysis using retroviral vectors. Curr. Top. Dev. Biol. 36, 51– 74 (1998).

    Article  CAS  Google Scholar 

  49. Sahel, J. A. et al. Mitogenic effects of excitatory amino acids in the adult rat retina. Exp. Eye Res. 53, 657– 664 (1991).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M.H. Baron for discussion and support throughout this project, S. Elledge, W. Harper and P. Zhang for cDNAs; J. Roberts and L.H. Tsai for knockout mice, and J. Zitz, M. Peters and L. Rose for technical support. M.A. Dyer was supported by NRSA fellowship # EY06803-02 and the Charles H. Revson Foundation Fellowship for Biomedical Research. This work was supported by National Institutes of Health Grant # EY0-8064.

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Correspondence to Constance L. Cepko.

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Dyer, M., Cepko, C. Control of Müller glial cell proliferation and activation following retinal injury. Nat Neurosci 3, 873–880 (2000). https://doi.org/10.1038/78774

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