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D.W. Rickman, P. Saloupis, B. Jessen, M.R. Niesman; The Pan Cyclin–Dependent Kinase Inhibitor, AG–012986, Perturbs Postnatal Retinal Development and Disrupts Photoreceptor Maintenance in the Differentiated Retina . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2972.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:CDK5 is expressed in numerous tissues and has homology to other CDKs that regulate cell cycling. However, its activity is localized to postmitotic neurons where, in concert with its activators p35 and p39, it is involved in processes of cell migration and synaptogenesis. To further elucidate the role of CDKs in retinal development, we examined the effects of a panCDK inhibitor with CDK5 antagonist activity on the postnatal differentiation of rat retinal explant cultures. Methods: Retinas were harvested from postnatal day 7 (P7) or P14 rats, plated onto nylon inserts and cultured for 7 days in control medium or medium supplemented with AG–012986 (10 ng/ml, 100 ng/ml or 1 µg/ml). Retinas were then processed for histological and immunohistochemical analyses using antibodies to the cell type–specific markers, rhodopsin, recoverin, PKC–a, parvalbumin or synaptophysin.Results: After 7 days in culture, untreated P7 explants displayed morphologies similar to the P14 retina in situ. This was accompanied by a normal compliment of retinal phenotypes, as identified by phenotypic markers. In drug treated cultures, retinal integrity was disrupted in a dose–dependent manner. At 10 ng/ml, the outer retina, including photoreceptor outer segments, was well–formed, as was the inner nuclear layer (INL). However, the inner plexiform layer was thin and disorganized, and the ganglion cell layer was largely acellular. At 100 ng/ml, the outer nuclear layer (ONL) was also dysmorphogenic, exhibiting only isolated patches of photoreceptors. At 1 µg/ml, the retinal structure was largely unrecognizable. This morphological continuum was paralleled by decreases in the normal patterning of retinal cell type–specific markers for photoreceptor, bipolar and amacrine cells, as well as the presynaptic protein, synaptophysin. In P14 retinas cultured for 7 days, untreated controls resembled mature retinas. Drug treated retinas displayed dose–dependent disruption of the retinal architecture. At 10 ng/ml this was confined to the ONL, but at higher concentrations the INL was also adversely affected. Again, morphological changes were mirrored by gross alterations in cellular phenotypes. Conclusions: In the early postnatal retina, CDK activity is important for normal retinal layering and patterning of retinal cellular phenotypes. Conversely, at later time points it is important in maintaining photoreceptor integrity. Based on its localization, these effects are most likely mediated by CDK5.
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