Department of Neurosurgery, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Department of Anatomy, Chungbuk National University College of Medicine, Chungbuk 28644, Republic of Korea.
Development. 2020 Sep 23;147(18):dev193094. doi: 10.1242/dev.193094.
The central nervous system (CNS) contains a complex network of blood vessels that promote normal tissue development and physiology. Abnormal control of blood vessel morphogenesis and maturation is linked to the pathogenesis of various neurodevelopmental diseases. The CNS-specific genes that regulate blood vessel morphogenesis in development and disease remain largely unknown. Here, we have characterized functions for the gene encoding prion protein 2 () in CNS blood vessel development and physiology. encodes the glycosylphosphatidylinositol (GPI)-linked protein doppel, which is expressed on the surface of angiogenic vascular endothelial cells, but is absent in quiescent endothelial cells of the adult CNS. During CNS vascular development, doppel interacts with receptor tyrosine kinases and activates cytoplasmic signaling pathways involved in endothelial cell survival, metabolism and migration. Analysis of mice genetically null for revealed impaired CNS blood vessel morphogenesis and associated endothelial cell sprouting defects. mice also displayed defects in endothelial barrier integrity. Collectively, these data reveal novel mechanisms underlying doppel control of angiogenesis in the developing CNS, and may provide new insights about dysfunctional pathways that cause vascular-related CNS disorders.
中枢神经系统 (CNS) 包含一个复杂的血管网络，促进正常组织发育和生理机能。血管形态发生和成熟的异常控制与各种神经发育疾病的发病机制有关。调节发育和疾病中血管形态发生的 CNS 特异性基因在很大程度上仍未知。在这里，我们描述了编码朊病毒蛋白 2 () 的基因在 CNS 血管发育和生理机能中的作用。编码糖基磷脂酰肌醇 (GPI) 连接蛋白 Doppel，它在血管生成的血管内皮细胞表面表达，但在成年 CNS 的静止内皮细胞中不存在。在 CNS 血管发育过程中，Doppel 与受体酪氨酸激酶相互作用，并激活涉及内皮细胞存活、代谢和迁移的细胞质信号通路。对基因敲除的小鼠进行分析显示，CNS 血管形态发生受损，伴有内皮细胞发芽缺陷。小鼠还表现出内皮屏障完整性缺陷。总的来说，这些数据揭示了 Doppel 控制发育中 CNS 血管生成的新机制，并可能为导致血管相关 CNS 疾病的功能失调途径提供新的见解。
