11-cis-retinal and Hyperplasia

The E2F1 transcription factor controls cell proliferation and apoptosis. E2F1 activity is negatively regulated by the retinoblastoma (RB) protein. To study how inactivation of Rb and dysregulated E2F1 affects the developing retina, we analysed wild-type and Rb(-/-) embryonic retinas and retinal transplants and we established transgenic mice expressing human E2F1 in retinal photoreceptor cells under the regulation of the IRBP promoter (TgIRBPE2F1). A marked increase in cell proliferation and apoptosis was observed in the retinas of Rb(-/-) mice and TgIRBPE2F1 transgenic mice. In the transgenic mice, photoreceptor cells formed rosette-like arrangements at postnatal days 9 through 28. Complete loss of photoreceptors followed in the TgIRBPE2F1 mice but not in the Rb(-/-) retinal transplants. Both RB-deficient and E2F1-overexpressing photoreceptor cells expressed rhodopsin, a marker of terminal differentiation. Loss of p53 partially reduced the apoptosis and resulted in transient hyperplasia of multiple cell types in the TgIRBPE2F1 retinas at postnatal day 6. Our findings support the concept that cross-talk occurs between different retinal cell types and that multiple genetic pathways must become dysregulated for the full oncogenic transformation of neuronal retinal cells.

Topics: Animals; Apoptosis; Cell Cycle; Cell Cycle Proteins; Cell Differentiation; Cell Division; DNA Replication; DNA-Binding Proteins; E2F Transcription Factors; E2F1 Transcription Factor; Eye Proteins; Female; Gene Expression Regulation; Genes, Synthetic; Humans; Hyperplasia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Photoreceptor Cells, Vertebrate; Promoter Regions, Genetic; Recombinant Fusion Proteins; Retina; Retinal Degeneration; Retinoblastoma Protein; Retinol-Binding Proteins; Rhodopsin; Transcription Factors; Transcription, Genetic; Transgenes