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D. Chen, R. Bremner; Role of E2f Family in Retinal Development. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5397. doi: https://doi.org/.
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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, However, cell cycle arrest following loss of activating E2f in Drosophila (dE2f1) can be rescued by deleting the repressor dE2f2, raising the issue of whether mammalian cells ever divide without E2f1-3. Our goal was to determine the effect and mechanism of inactivating E2f1, E2f2, and/or E2f3 on retinal development.
E2f1-/-, E2f2-/-, E2f3loxP/loxP, N-MycloxP/loxP and P53loxP/loxP mice were interbred with alpha-Cre mice. The latter transgenic strain expresses Cre recombinase specifically in the peripheral retina from E9.5. Single knockout, double knockout (DKO), triple knockout (TKO) and quadruple knockout (QKO) retinas were assessed for cell division, death and differentiation by Brdu/PH3/Ki67 labeling, TUNEL labeling and cell type marker immunofluorescence at various embryonic and post-natal ages.
In stark contrast to fibroblasts, E2f1-3 triple null (TKO) retinal progenitor cells (RPCs) and activated Müller glia continue to divide, and late stage TKO RPCs show elevated apoptosis. Reduced proliferation in TKO RPCs is not, as in fibroblasts, rescued by deletion of p53. However, p53 does drive elevated apoptosis. Continued RPC division is N-Myc dependent, thus E2f1-3/NMyc quadruple null (QKO) RPCs arrest almost completely. In 5 genotypes with progressively slower RPC division (p27KO>WT>E2f1KO> E2f1-3TKO>E2f1-3/NMyc) the timing of cell birth is unaffected except in the QKO retina where division is almost stopped.
First, E2f1-3 are not indispensable for proliferation in the retina. In the absence of E2f1-3, N-Myc drives the division of retinal progenitor cells. Second, E2f1-3 can suppress RPC apoptosis. In the absence of E2f1-3, RPCs die through a p53-dependent pathway. Third, above a low minimal threshold, proliferation does not affect RPC differentiation.
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