p27(Kip1) and p57(Kip2) regulate proliferation in distinct retinal progenitor cell populations

In the developing vertebrate retina, progenitor cell proliferation must be precisely regulated to ensure appropriate formation of the mature tissue. C yclin kinase inhibitors have been implicated as important regulators of pro liferation during development by blocking the activity of cyclin-cyclin-dep endent kinase complexes. We have found that the p27(Kip1) cyclin kinase inh ibitor regulates progenitor cell proliferation throughout retinal histogene sis. p27(Kip1) is upregulated during the late G(2)/early G(1) phase of the cell cycle in retinal progenitor cells, where it interacts with the major r etinal D-type cyclin-cyclin D1. Mice deficient for p27(Kip1) exhibited an i ncrease in the proportion of mitotic cells throughout development as well a s extensive apoptosis, particularly during the later stages of retinal hist ogenesis. Retroviral-mediated overexpression of p27(Kip1) in mitotic retina l progenitor cells led to premature cell cycle exit yet had no dramatic eff ects on Muller glial or bipolar cell fate specification as seen with the Xe nopus cyclin kinase inhibitor, p27(Xic1). Consistent with the overexpressio n of p27(Kip1), mice lacking one or both alleles of p27(Kip1) maintained th e same relative ratios of each major retinal cell type as their wild-type l ittermates. During the embryonic stages of development, when both p27(Kip1) and p57(Kip2) are expressed in retinal progenitor cells, they were found i n distinct populations, demonstrating directly that different retinal proge nitor cells are heterogeneous with respect to their expression of cell cycl e regulators.