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Regulating proliferation during retinal development

Nature Reviews Neuroscience volume 2, pages 333–342 (2001)Cite this article

Key Points

  • The control of the cell cycle is vital in determining the size of an organism and the size and cellular makeup of its individual organs. The vertebrate retina is a valuable model for studying cell-cycle regulation, because retinal progenitor cells generate a variety of cell types in a highly stereotypical manner, requiring precise coordination of cell proliferation and cell-cycle exit.

  • Cell proliferation during development of the central nervous system (CNS) is regulated by a combination of intrinsic and extrinsic factors. Early during development, extrinsic factors signal progenitor cells to upregulate genes that drive cell cycle progression, or to downregulate genes that encourage cell-cycle exit. Later, the emphasis is shifted towards promoting cell-cycle exit or decreasing the production of mitosis-promoting factors.

  • After M phase, progenitor cells decide either to undergo a further round of proliferation or to terminally differentiate. In cells that continue to proliferate, the retinoblastoma (Rb) protein or a related family member becomes phosphorylated by a cyclin–cyclin-dependent kinase complex. This phosphorylation step is blocked if the cell decides to exit the cell cycle.

  • Cyclin-kinase inhibitors (CKIs) have diverse roles in the CNS. p27Xic1, a Xenopus protein that belongs to the Cip/Kip family, regulates proliferation, Müller glia cell-fate specification and possibly bipolar fate specification, whereas the rodent equivalent p27Kip1 primarily regulates cell-cycle exit. Like p27Xic1, the rodent p57Kip2 has a dual role, regulating both cell-cycle exit and specification of amacrine cells in the postnatal retina.

  • Retinal progenitor cells are heterogeneous in their expression of components of the cell-cycle machinery (for example, p27Kip1 versus p57Kip2, or cyclin D1 versus cyclin D3). This could reflect intrinsic differences between progenitor cells, or extracellular cues might instruct them to exit the cell cycle at different times.

  • In the rodent retina, cell-cycle exit is a two-step process: cyclin D1 is downregulated, then one of the CKIs is upregulated. Cyclin D1 knockout mice show reduced retinal progenitor cell proliferation, whereas p27Kip1- or p57Kip2-deficient mice show extra cell division in the retina. In mice deficient for both cyclin D1 and p27Kip1, the retina develops normally.

  • Progenitor cells possess mechanisms to compensate for perturbations in the cell-cycle machinery; for example, the effects of the cyclin D1 knockout are partially counteracted by the upregulation of cyclin D3. By contrast, there is no known mechanism to compensate for mutations in Rb.

  • Apoptosis can also compensate for the deregulation of proliferation; for example, in CKI knockout mice, increased apoptosis is seen in the inner neuroblastic layer of the retina.

  • During stress or injury, glial cells in the adult CNS can be induced to divide. After retinal injury, p27Kip1 is downregulated and Müller glia re-enter the cell cycle. To prevent uncontrolled proliferation, they downregulate cyclin D3 and upregulate glial fibrillary acidic protein. In p27Kip1-deficient mice, Müller glia initiate reactive gliosis during the final stages of retinal development, leading to retinal dysplasia. Knocking out p27Kip1 produces the same changes in protein levels as injury, indicating that p27Kip1 downregulation is critical to regulate Müller cell proliferation.

Abstract

Recent studies have shown that components of the cell-cycle machinery can have diverse and unexpected roles in the retina. Cyclin-kinase inhibitors, for example, have been implicated as regulators of cell-fate decisions during histogenesis and reactive gliosis in the adult tissue after injury. Also, various mechanisms have been identified that can compensate for extra rounds of cell division when the normal timing of the cell-cycle exit is perturbed. Surprisingly, distinct components of the cell-cycle machinery seem to be used during different stages of development, and different organisms might rely on distinct pathways. Such detailed studies on the regulation of proliferation in complex multicellular tissues during development have not only advanced our knowledge of the ways in which proliferation is controlled, but might also help us to understand the degenerative disorders that are associated with gliosis and some types of tumorigenesis.

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Figure 1: Families of related proteins regulate cell-cycle progression during G1.
Figure 2: p27Kip1 and p57Kip2 are upregulated during different phases of the cell cycle in distinct retinal progenitor-cell populations.
Figure 3: The cyclin D1−/− mouse retina shows a unique form of retinal degeneration.
Figure 4: p57Kip2 is important for amacrine sub-population development.
Figure 5: Apoptosis compensates for deregulated proliferation in cyclin-kinase-inhibitor-deficient retinae.
Figure 6: p27Kip1 regulates cell-cycle exit in Müller glial cells after retinal injury.

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Acknowledgements

We would like to thank Margaret H. Baron for continued support, Brenda L. Gallie and Rod Bremner for sharing pre-publication results, and Seo-Hee Cho for critical reading of the manuscript. Research support was from the National Eye Institute. A grant from the NRSA grant and the Charles H. Revson fellowship for biomedical research supported M.A.D.

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Authors and Affiliations

  1. Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, 200 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Michael A. Dyer & Constance L. Cepko

  2. Michael A. Dyer & Constance L. Cepko

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DATABASE LINKS

EGF

FGF

Rb

p27Kip1

cyclin D1

p57Kip2

cyclin D3

p19

p107

GFAP

ENCYCLOPEDIA OF LIFE SCIENCES

Visual system development in vertebrates

Cell cycle: regulation by cyclins

Glossary

DYSPLASIA

Premalignant change characterized by alteration in size, shape and organization of the cellular elements of a tissue.

MÜLLER GLIA

The main glial cell type present in the retina.

BROMODEOXYURIDINE

Thymidine analogue that incorporates into the DNA of dividing cells.

RETROVIRUS

Virus composed of single-stranded RNA enclosed by a protein capsid and surrounded by a lipid envelope.

CALBINDIN

Calcium-binding protein that might function as a calcium buffer.

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Dyer, M., Cepko, C. Regulating proliferation during retinal development. Nat Rev Neurosci 2, 333–342 (2001). https://doi.org/10.1038/35072555

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