Mfsd2a is critical for the formation and function of the blood-brain barrier.
Mfsd2a is critical for the formation and function of the blood-brain barrier.
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DOI：
10.1038/nature13324
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发表时间：
2014-05-22
期刊：
影响因子：
64.8
通讯作者：
Gu, Chenghua
中科院分区：
文献类型：
--
作者：
Ben-Zvi, Ayal;Lacoste, Baptiste;Kur, Esther;Andreone, Benjamin J.;Mayshar, Yoav;Yan, Han;Gu, Chenghua
中枢神经系统（CNS）需要一个严格控制的环境，没有毒素和病原体，以提供适当的化学成分的神经功能。这种环境是由“血脑屏障”（BBB）维持的，它由血管组成，血管的内皮细胞表现出特殊的紧密连接和极低的跨细胞囊泡运输率（胞吞作用）。与周细胞和星形胶质细胞一起，这种独特的脑内皮生理屏障封闭中枢神经系统并控制物质的流入和流出。虽然血脑屏障的破坏最近与各种神经系统疾病的发生和延续有关，但完整的血脑屏障是药物递送到中枢神经系统的主要障碍。对控制血脑屏障形成的分子机制的有限理解阻碍了我们在疾病和治疗中操纵血脑屏障的能力。在这里，我们确定了控制建立功能性血脑屏障的机制。首先，使用一种新的胚胎示踪剂注射方法，我们展示了血脑屏障功能的时空发育特征，并发现小鼠血脑屏障在胚胎期15.5天（E15.5）开始具有功能。然后，我们筛选血脑屏障形成过程中表达的BBB特异性基因，发现含有主要促进物超家族结构域2a （Mfsd2a）在中枢神经系统含BBB的血管中选择性表达。基因消融Mfsd2a导致从胚胎期到成年期血脑屏障渗漏，同时维持血管网络的正常模式。电镜检查显示Mfsd2a - / -小鼠中枢神经系统内皮细胞囊泡胞吞明显增加，无明显紧密连接缺陷。最后，我们发现MFSD2A内皮表达受周细胞调节，以促进血脑屏障的完整性。这些发现表明MFSD2A是血脑屏障功能的关键调节因子，可能通过抑制中枢神经系统内皮细胞的胞吞作用起作用。此外，我们的发现可能有助于开发中枢神经系统药物输送的治疗方法。
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. While 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 embryonic tracer injection method, 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 periods through adulthood, while maintaining the normal patterning of vascular networks. 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. Further our findings may aid in efforts to develop therapeutic approaches for CNS drug delivery.
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