Nature2014-06-17 5:07 PM

Mfsd2a在血-脑屏障中所起作用2 Mfsd2a is critical for the formation and function of the blood–brain barrier

论文摘要 

血-脑屏障在为脑功能维持必要环境中起至关重要的作用,但对于以脑为方向的治疗药物却是一个不方便的障碍。本期Nature上发表的两篇论文报告了Mfsd2a (主要促进因子超级家族的一个成员,以前被认为是一个“孤儿运输因子”)在血-脑屏障功能的两个方面中的参与情况。David Silver及同事识别出Mfsd2a是奥米伽脂肪酸“二十二碳六烯酸”(DHA)向脑中吸收的主要运输因子。Mfsd2a只在血-脑屏障的内皮中表达,Mfsd2a被剔除的小鼠脑中DHA水平降低、神经元数量减少、脑大小和功能降低。Chenghua Gu及同事发现Mfsd2起血-脑屏障发育和功能的一个调控因子的作用:该屏障在缺失Mfsd2a的小鼠中会变得有泄漏,这可能是跨细胞的小泡运输量增加所造成的一个结果。

Abstract 

The central nervous system (CNS) requires a tightly controlled environment free of toxins and pathogens to provide the proper chemical composition for neural function. This environment is maintained by the ‘blood–brain barrier’ (BBB), which is composed of blood vessels whose endothelial cells display specialized tight junctions and extremely low rates of transcellular vesicular transport (transcytosis). In concert with pericytes and astrocytes, this unique brain endothelial physiological barrier seals the CNS and controls substance influx and efflux. Although BBB breakdown has recently been associated with initiation and perpetuation of various neurological disorders, an intact BBB is a major obstacle for drug delivery to the CNS. A limited understanding of the molecular mechanisms that control BBB formation has hindered our ability to manipulate the BBB in disease and therapy. Here we identify mechanisms governing the establishment of a functional BBB. First, using a novel tracer-injection method for embryos, we demonstrate spatiotemporal developmental profiles of BBB functionality and find that the mouse BBB becomes functional at embryonic day 15.5 (E15.5). We then screen for BBB-specific genes expressed during BBB formation, and find that major facilitator super family domain containing 2a (Mfsd2a) is selectively expressed in BBB-containing blood vessels in the CNS. Genetic ablation of Mfsd2a results in a leaky BBB from embryonic stages through to adulthood, but the normal patterning of vascular networks is maintained. Electron microscopy examination reveals a dramatic increase in CNS-endothelial-cell vesicular transcytosis in Mfsd2a−/− mice, without obvious tight-junction defects. Finally we show that Mfsd2a endothelial expression is regulated by pericytes to facilitate BBB integrity. These findings identify Mfsd2a as a key regulator of BBB function that may act by suppressing transcytosis in CNS endothelial cells. Furthermore, our findings may aid in efforts to develop therapeutic approaches for CNS drug delivery.

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