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The Journal of Neuroscience, June 15, 2001, 21(12):4259-4271

p27^Kip1 and p57^Kip2 Regulate Proliferation in Distinct Retinal Progenitor Cell Populations

Michael A. Dyer and Constance L. Cepko

Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115

In the developing vertebrate retina, progenitor cell proliferation must be precisely regulated to ensure appropriate formation of the mature tissue. Cyclin kinase inhibitors have been implicated as important regulators of proliferation during development by blocking the activity of cyclin-cyclin-dependent kinase complexes. We have found that the p27^Kip1 cyclin kinase inhibitor regulates progenitor cell proliferation throughout retinal histogenesis. p27^Kip1 is upregulated during the late G₂/early G₁ phase of the cell cycle in retinal progenitor cells, where it interacts with the major retinal D-type cyclin-cyclin D1. Mice deficient for p27^Kip1 exhibited an increase in the proportion of mitotic cells throughout development as well as extensive apoptosis, particularly during the later stages of retinal histogenesis. Retroviral-mediated overexpression of p27^Kip1 in mitotic retinal progenitor cells led to premature cell cycle exit yet had no dramatic effects on Müller glial or bipolar cell fate specification as seen with the Xenopus cyclin kinase inhibitor, p27^Xic1. Consistent with the overexpression of p27^Kip1, mice lacking one or both alleles of p27^Kip1 maintained the same relative ratios of each major retinal cell type as their wild-type littermates. During the embryonic stages of development, when both p27^Kip1 and p57^Kip2 are expressed in retinal progenitor cells, they were found in distinct populations, demonstrating directly that different retinal progenitor cells are heterogeneous with respect to their expression of cell cycle regulators.

Key words: cyclin kinase inhibitor; apoptosis; cyclin D1; retrovirus; Müller glia; bipolar cell

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21124259-13$05.00/0

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