Unexpected Effects of E2F1–3 Deletion on Retinal Cell Proliferation and Apoptosis

Abstract

Abstract: : Purpose: To study the biological roles of E2F1, E2F2 and E2F3 in mouse retina. Methods: Knocking out E2F1–3 in mouse retina Results: The RB pathway has a critical role in the control of cellular proliferation by regulating E2F activity. E2F1, E2F2 and E2F3 belong to a subclass of E2F factors–the"activating E2Fs"– thought to act as transcriptional activators important for progression through the G1/S transition. Based primarily on studies in knockout fibroblasts, it was widely believed that E2F1–3 are indispensable for proliferation. In addition, the activating E2Fs have been linked to the induction of apoptosis in a wide variety of cell types. Here we show that, in stark contrast to current dogma, retinas lacking E2F1–3 continue to grow and differentiate, albeit at a reduced rate. Moreover, these retinas exhibit enhanced apoptosis around birth and, while E2F1–3 are not required for the differentiation of any retinal cell types, mature ganglion cells are lost between p10–p18. Retinas lacking E2F1–3 also form extensive holes in the photoreceptor layer after P8. This phenotype is almost identical to that seen in the cyclin D1 null retina. Conclusions: (1) An E2F1–3–independent pathway can partially rescue proliferation in the retina; (2) E2F1–3 have an unexpected role in retinal cell survival; (3) Cyclin D1 regulates retinal development through E2F1–3. Studies on E2F1–3 triple knockout retina may enhance our understanding on molecular mechanism, and/or improve current treatment, of retinal degeneration, retinal detachment, glaucoma and retinoblastoma

Keywords: apoptosis/cell death • photoreceptors • ganglion cells