Tailless and hypoxia inducible factor-2α cooperate to sustain proangiogenic states of retinal astrocytes in neonatal mice.
Tailless and hypoxia inducible factor-2α cooperate to sustain proangiogenic states of retinal astrocytes in neonatal mice.
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Tailless（TLX，一种孤儿核受体）和缺氧诱导因子 2α（HIF2α）对于视网膜星形胶质细胞和血管发育都是必需的。已知 Hif2αf/f/GFAPCre 小鼠中的 Tlx−/− 突变和星形胶质细胞特异性 Hif2α 破坏会导致星形胶质细胞发育缺陷并阻碍新生儿视网膜的血管发育。在此，我们报道 TLX 和 HIF2α 通过协同维持视网膜星形胶质细胞处于促血管生成状态来支持视网膜血管生成。虽然 Tlx+/- 和 Hif2αf/+/GFAPCre 小鼠表型正常，但 Tlx+/-/Hif2αf/+/GFAPCre 小鼠表现出早熟的视网膜星形胶质细胞向非血管生成状态分化，同时视网膜血管生成显着减少。在野生型小鼠中，TLX 和 HIF2α 共存于同一蛋白质复合物中，表明在生理条件下具有协同功能。此外，星形胶质细胞特异性破坏 Phd2（脯氨酰羟化酶结构域蛋白 2）（之前显示这种操作会导致 HIF2α 积累）并不能挽救 Tlx−/− 背景下的视网膜血管生成，这表明 HIF2α 对 TLX 的功能依赖性。最后，新生 Tlx+/-/Hif2αf/+/GFAPCre 小鼠视网膜星形胶质细胞中纤连蛋白和 VEGF-A 的表达显着降低。总体而言，这些数据表明 TLX 和 HIF2α 通过维持视网膜星形胶质细胞的血管生成潜力来协同支持视网膜血管生成。摘要：视网膜星形胶质细胞成熟后会失去支持血管生成的能力。 Tlx 和 HIF-2α 之间的蛋白质-蛋白质相互作用使视网膜星形胶质细胞维持在促血管生成祖细胞和未成熟状态。
Tailless (TLX, an orphan nuclear receptor) and hypoxia inducible factor-2α (HIF2α) are both essential for retinal astrocyte and vascular development. Tlx−/− mutation and astrocyte specific Hif2α disruption in Hif2αf/f/GFAPCre mice are known to cause defective astrocyte development and block vascular development in neonatal retinas. Here we report that TLX and HIF2α support retinal angiogenesis by cooperatively maintaining retinal astrocytes in their proangiogenic states. While Tlx+/− and Hif2αf/+/GFAPCre mice are phenotypically normal, Tlx+/−/Hif2αf/+/GFAPCre mice display precocious retinal astrocyte differentiation towards non-angiogenic states, along with significantly reduced retinal angiogenesis. In wild-type mice, TLX and HIF2α coexist in the same protein complex, suggesting a cooperative function under physiological conditions. Furthermore, astrocyte specific disruption of Phd2 (prolyl hydroxylase domain protein 2), a manipulation previously shown to cause HIF2α accumulation, did not rescue retinal angiogenesis in Tlx−/− background, which suggests functional dependence of HIF2α on TLX. Finally, the expression of fibronectin and VEGF-A is significantly reduced in retinal astrocytes of neonatal Tlx+/−/Hif2αf/+/GFAPCre mice. Overall, these data indicate that TLX and HIF2α cooperatively support retinal angiogenesis by maintaining angiogenic potential of retinal astrocytes. Summary: Retinal astrocytes lose their ability to support angiogenesis as they mature. Protein–protein interaction between Tlx and HIF-2α maintains retinal astrocytes in their proangiogenic progenitor and immature states.
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影响因子：
2.4
作者：
Zeng ZJ;Johansson E;Hayashi A;Chavali PL;Akrap N;Yoshida T;Kohno K;Izumi H;Funa K
通讯作者：
Funa K
影响因子：
64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
2.5
作者：
LING, TL;MITROFANIS, J;STONE, J
通讯作者：
STONE, J
DOI：
10.1242/dev.199418
发表时间：
2021-05-01
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Perelli RM;O'Sullivan ML;Zarnick S;Kay JN
通讯作者：
Kay JN
影响因子：
5.3
作者：
Takeda, Kotaro;Ho, Vivienne C.;Fong, Guo-Hua
通讯作者：
Fong, Guo-Hua