Rb is required for retinal angiogenesis and lamination
Retinoblastoma tumor suppressor (Rb) promotes cell cycle exit, survival, differentiation, and tumor suppression in the retina. Here, we show it is also essential for vascularization and lamination. Despite minimal effects on Hif1a target expression, intraretinal vascular plexi did not form in the Rb−/− murine retina. Deleting adenovirus E2 promoter binding factor 3 (E2f3), which rescues starburst amacrine cell differentiation, or E2f2, had no effect, but deleting E2f1, which promotes neuronal cell cycle exit and survival, restored retinal vasculature. We specifically linked cell loss to the defect because removing Bax rescued rod and bipolar neurons and the vasculature, but not cell cycle exit. Despite rescuing Rb−/− neurons, Bax deletion exacerbated a delay in outer retina lamination, and exposed a requirement for Rb in inner retina lamination. The latter resembled Sem5 or FAT atypical cadherin 3 (Fat3) mutants, but expression of Sem5/Fat3 pathway components, or that of Neogenin, which perturbs migration in the Rb−/− cortex, was unchanged. Instead, lamination defects correlated with ectopic division, and were E2f1-dependent, implicating the cell cycle machinery. These in vivo studies expose new developmental roles for Rb, pinpoint aberrant E2f1 and Bax activity in neuronal death and vascular loss, and further implicate E2f1 in defective lamination. Links between Rb, angiogenesis and lamination have implications for the treatment of neovascularization, neurodegeneration and cancer.
[…] The dataset GSE86372 at NCBI GEO database (http://www.ncbi.nlm.nih.gov/geo/) was used to compare WT vs. RbKO mouse P8 retinas, which include three WT and three RbKO mouse P8 retinas. The data were analyzed by GEO2R from the GEO website. The genes, of which expression fold changes are >2 or <0.5, and adjusted p < 0.05 were selected as the RbKO-related DEGs. Totally 677 DEGs were identified. The heatmap was generated using Heatmapper. The function enrichment of DEG was performed using Enrichr,, the pathways with adjusted p < 0.05 were chosen to report. […]
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