TY - JOUR AU - Wei, Ran AU - Ren, Xiang AU - Kong, Hongyu AU - Lv, Zhongping AU - Chen, Yongjiang AU - Tang, Yunjing AU - Wang, Yujiao AU - Xiao, Lirong AU - Yu, Tao AU - Hacibekiroglu, Sabiha AU - Liang, Chen AU - Nagy, Andras AU - Bremner, Rod AU - Chen, Danian T1 - Rb1/Rbl1/Vhl loss induces mouse subretinal angiomatous proliferation and hemangioblastoma PY - 2019/11/14/ AB - Von Hippel–Lindau (Vhl) protein inhibits hypoxia-inducible factor (Hif), yet its deletion in murine retina does not cause the extensive angiogenesis expected with Hif induction. The mechanism is unclear. Here we show that retinoblastoma tumor suppressor (Rb1) constrains expression of Hif target genes in the Vhl–/– retina. Deleting Rb1 induced extensive retinal neovascularization and autophagic ablation of photoreceptors in the Vhl–/– retina. RNA-sequencing, ChIP, and reporter assays showed Rb1 recruitment to and repression of certain Hif target genes. Activating Rb1 by deleting cyclin D1 induced a partial defect in the retinal superficial vascular plexus. Unexpectedly, removing Vhl suppressed retinoblastoma formation in murine Rb1/Rbl1–deficient retina but generated subretinal vascular growths resembling retinal angiomatous proliferation (RAP) and retinal capillary hemangioblastoma (RCH). Most stromal cells in the RAP/RCH–like lesions were Sox9+, suggesting a Müller glia origin, and expressed Lgals3, a marker of human brain hemangioblastoma. Thus, the Rb family limit Hif target gene expression in the Vhl–/– retina, and removing this inhibitory signal generates new models for RAP and RCH. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.127889 VL - 4 IS - 22 UR - https://doi.org/10.1172/jci.insight.127889 PB - The American Society for Clinical Investigation ER -