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{"project":"2_test","denotations":[{"id":"17608565-9420334-84868979","span":{"begin":224,"end":226},"obj":"9420334"},{"id":"17608565-8381715-84868979","span":{"begin":224,"end":226},"obj":"8381715"},{"id":"17608565-11545733-84868979","span":{"begin":224,"end":226},"obj":"11545733"},{"id":"17608565-8946919-84868979","span":{"begin":224,"end":226},"obj":"8946919"},{"id":"17608565-15193257-84868980","span":{"begin":1093,"end":1094},"obj":"15193257"},{"id":"17608565-15193257-84868981","span":{"begin":1837,"end":1838},"obj":"15193257"},{"id":"T28719","span":{"begin":224,"end":226},"obj":"9420334"},{"id":"T5228","span":{"begin":224,"end":226},"obj":"8381715"},{"id":"T83773","span":{"begin":224,"end":226},"obj":"11545733"},{"id":"T51839","span":{"begin":224,"end":226},"obj":"8946919"},{"id":"T23743","span":{"begin":1093,"end":1094},"obj":"15193257"},{"id":"T30099","span":{"begin":1837,"end":1838},"obj":"15193257"}],"text":"Normal Function of the Rb/E2f1 DKO Retina\nThe discovery that E2f1 loss rescues even the morphology of Rb KO neurons is surprising because Rb is thought to regulate differentiation primarily through E2f-independent pathways [30–33]. However, normal morphology may not equate to completely normal differentiation. Thus, we compared the electroretinograms (ERGs) of adult WT (α-Cre), E2f1−/−, α-Cre;RbloxP/loxP, and α-Cre;RbloxP/loxP;E2f1−/− mice. ERGs functionally assess visual signalling in the mammalian retina from photoreceptors to amacrine cells (but usually not gangion cells), and are dominated by rod and cone bipolar cells. Typically, an ERG signal begins with a negative deflection initiated by the photoreceptors (the a-wave), which is terminated by a large positive deflection due to the activation of ON bipolar cells (the b-wave).\nResponses to dim light in dark-adapted (scotopic) conditions specifically assess the rod system, and were defective in the Rb KO retina (Figure 2E). The substantial reduction of both a- and b-waves is consistent with rod and bipolar cell apoptosis [2]. The sensitivity of the residual response appeared unchanged, suggesting it arose from the Cre-negative portions of the retina. Responses were about the same in the WT and E2f1 KO retina, and, most importantly, also the Rb/E2f1 DKO response median lay at the lower end of the normal range for most intensities (Figure 2F). Thus, E2f1 deletion almost completely rescued the rod system in the Rb KO retina.\nLight-adapted (photopic) recordings to specifically assess the cone system yielded comparable results. Cones represent only 3% of photoreceptors and, unlike rods, develop without Rb, but they require rods for survival, and in the Rb KO retina, they have abnormal morphology and their synaptic targets, bipolar cells, are much depleted [2]. The photopic response, a product of cone and mainly bipolar activity, was much reduced by Rb loss, but was rescued considerably in the Rb/E2f1 DKO retina (Figure S5). Again, the median amplitude lay at the lower end of the E2f1 KO range. The photopic response in E2f1 KO mice was slightly reduced relative to WT (Figure S5B), possibly because E2f1 is required for maximal expansion of embryonic RPCs, and the E2f1 KO retina has, as noted earlier, slightly fewer cells than the WT retina, although cell type proportions are unaffected (D. C. and R. B., unpublished data). Thus, marginally subnormal photopic responses in the Rb/E2f1 DKO retina can be attributed to both a reduction of cone numbers in E2f1 KO mice alone, and a “genuine” slight reduction in cone function attributable to Rb loss relative to WT. This slight effect may relate to a true differentiation defect in a subset of amacrine cells discussed below. This discussion should not obscure the major outcome that E2f1 deletion recovers most of the ERG response. Thus, E2f1 deletion not only rescues morphology but also both rod and cone system function in the Rb KO retina."}

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PMC:1914394 / 19681-22660 JSON TXT