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R. Bremner, D. Chen, M. Agochiya, G. Leone, Z. Ni; Role of the E2F Family in Retinal Development . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3528.
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Purpose: Coordination of the cell cycle and differentiation is critical to produce the correct numbers and types of cells in the developing retina. The activating E2Fs (E2F1, E2F2 and E2F3) are indispensable for proliferation in primary fibroblasts, but their combined role in any tissue in vivo is unknown. Our goal was to determine the effect of inactivating E2F1, E2F2, and/or E2F3 on retinal development. Methods: E2F1–/–, E2F2–/– and E2F3loxP/loxP mice were interbred with alpha–Cre mice. The latter transgenic strain expresses Cre recombinase specifically in the peripheral retina from E9. Single knockout, double knockout (DKO) and triple knockout (TKO) retinas were assessed for cell division, death and differentiation at various embryonic and post–natal ages. Results: In stark contrast to fibroblasts, retinal progenitor cells (RPCs) did not completely arrest following inactivating of E2F1–3. Retinal cell number was reduced 6–fold, but there was significant division throughout the normal period of retinogenesis. Of the three transcription factors, E2F1 was the only member which, on its own, was critical for maximal division. Its loss reduced cell number 2.5 fold. The combined loss of E2F2 and 3 did not affect RPC division. Despite the known role of E2Fs in inducing apoptosis, post–natal TKO RPCs exhibited elevated apoptosis. E2F loss did not, however, affect the survival of differentiating retinal cells as all seven major retinal cell types form normally in the TKO retina. Notably, however, photoreceptor holes form in the retina after P10, akin to the phenotype in the cyclin D1 KO retina. Conclusions: First, E2F1–3 are not indispensable for proliferation in the retina. We are investigating the molecular differences between cell cycle components in RPCs versus fibroblasts that may explain this difference. Second, E2F1–3 increases RPC apoptosis. We are investigating the role of the p53 pathway in this process. Third, E2F1–3 are required for the survival of post–mitotic photoreceptors. We are investigating whether this reflects a direct role for E2Fs in these neurons. In summary, deletion of the activating E2Fs has diverse and unexpected roles in retinal development
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