Rb1/Rbl1/Vhl loss induces mouse subretinal angiomatous proliferation and hemangioblastoma
Rb1/Rbl1/Vhl loss induces mouse subretinal angiomatous proliferation and hemangioblastoma
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Rb1/Rbl1/Vhl 缺失诱导小鼠视网膜下血管瘤增殖和血管母细胞瘤
DOI：
10.1172/jci.insight.127889
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发表时间：
2019
期刊：
影响因子：
8
通讯作者：
Danian Chen
中科院分区：
文献类型：
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作者：
Ran Wei;Xiang Ren;Hongyu Kong;Zhongping Lv;Yongjiang Chen;Yunjing Tang;Yujiao Wang;Lirong Xiao;Tao Yu;Sabiha Hacibekiroglu;Chen Liang;Andras Nagy;Rod Bremner;Danian Chen
Von Hippel-Lindau(VHL)蛋白抑制低氧诱导因子(HIF)，但其在小鼠视网膜中的缺失并不会导致HIF诱导的广泛血管生成。其机制尚不清楚。在这里，我们发现视网膜母细胞瘤肿瘤抑制因子(Rb1)限制了Hif靶基因在VHL-/-视网膜中的表达。删除Rb1诱导了广泛的视网膜新生血管和VHL-/-视网膜中光感受器的自噬消融。RNA测序、芯片和报告分析表明，Rb1对某些Hif靶基因有募集和抑制作用。通过删除细胞周期蛋白D1来激活Rb1，导致视网膜浅血管丛(SVP)部分缺失。出乎意料的是，移除VHL抑制了Rb1/Rbl1缺陷小鼠视网膜上视网膜母细胞瘤的形成，但产生了类似视网膜血管瘤样增殖(RAP)和视网膜毛细血管母细胞瘤(RCH)的视网膜下血管生长。在RAP/RCH样病变中，大多数基质细胞为Sox9+，提示为Müler胶质细胞起源，并表达人脑血管母细胞瘤的标志物Lgals3。因此，Rb家族限制了Hif靶基因在VHL-/-视网膜中的表达，而去除这种抑制信号将为RAP和RCH产生新的模型。
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 (SVP). 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.