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Danian Chen, Rod Bremner; E2f And Mycn Regulate Retinal Differentiation Through Notch Pathway. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6004.
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© ARVO (1962-2015); The Authors (2016-present)
Coordination of the cell cycle and differentiation is essential to produce the proper numbers and types of cells in the developing retina. The activating E2fs and Mycn are indispensable for proliferation of mouse retinal progenitors. However their roles in retinal differentiation are not clear yet. Our goal was to determine the effect and mechanism of inactivating E2fs and Mycn on retinal differentiation.
E2f1-/-, E2f2-/-, E2f3 loxP/loxP, MycnloxP/loxP mice were interbred with alpha-Cre mice. The transgenic alpha-Cre recombinase specifically expresses in the peripheral retina from E9.5. Retrovirus injection or plasmids electroporation were applied to deliver expression vectors of GFP-Cre, GFP control, Hes1 and Notch1 intracellular domain (NIC) into the subretinal space of newborn pups. 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.
Decreasing progenitor proliferation in E2f1KO, E2f1-3TKO and E2f1-3/Mycn quadruple null (QKO) causes a switch to early born neurons only in an extreme case (E2f1-3/Mycn QKO). Inactivating E2f1-3/N-Myc in early retinal progenitor cells (RPC) resulted in proliferation arrest and cell cycle exit, and those QKO retinas only generated early born neurons (ganglions, cones, horizontal and amacrine cells) in the expenses of late-born cells (rod, bipolar and Müller glia). Notch pathway (Notch1, Hes1, Hes5, and Hey1) was down-regulated, and Math5, Prox1 and Trb2 were up-regulated in QKO retinas. Inactivating E2f1-3/Mycn in late RPC by Cre retrovirus or plasmid resulted in more rod cells in the expense of bipolar and Müller glia. Over-expression Hes1 or NIC can override this defect.
1. Above a low threshold, proliferation rate per se does not influence neurogenesis. 2. E2f1-3 and Mycn redundantly regulate the cell cycle machinery and Notch pathway in RPCs, thus control and coordinate retinal proliferation and differentiation.
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