Mfsd2a is critical for the formation and function of the blood–brain barrier

• Published in: Nature (London) 2014-05, Vol.509 (7501), p.507-511
• Main Authors: Ben-Zvi, Ayal, Lacoste, Baptiste, Kur, Esther, Andreone, Benjamin J., Mayshar, Yoav, Yan, Han, Gu, Chenghua
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/31; 13/51; 14; 14/1; 14/19; 14/28; 14/34; 38; 38/39; 38/61; 38/77; 45; 45/29; 45/61; 45/77; 631/378/1341; 64; 64/110; 64/60; 96; Animals; Blood pressure; Blood Vessels - metabolism; Blood-brain barrier; Blood-Brain Barrier - embryology; Blood-Brain Barrier - physiology; Carrier proteins; Central nervous system; Cerebral Cortex - blood supply; Cerebral Cortex - embryology; Cerebral Cortex - metabolism; Drug Delivery Systems; Embryos; Endothelial Cells - metabolism; Endothelium; Female; Gene Expression Profiling; Genetic aspects; Humanities and Social Sciences; letter; Male; Membrane proteins; Membrane Transport Proteins - deficiency; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Methods; Mice; Microscopy; multidisciplinary; Neovascularization, Physiologic; Observations; Pericytes - metabolism; Physiological aspects; Proteins; Rodents; Science; Spatio-Temporal Analysis; Tight Junctions - metabolism; Tight Junctions - pathology; Toxins; Transcytosis; Vascular endothelium
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13324

Mfsd2a is a key regulator of blood–brain barrier (BBB) formation and function in mice: Mfsd2a is selectively expressed in BBB-containing blood vessels in the CNS; Mfsd2a −/− mice have a leaky BBB and increased vesicular transcytosis in CNS endothelial cells; and Mfsd2a endothelial expression is regulated by pericytes to facilitate BBB integrity. Building the blood–brain barrier The blood–brain barrier serves a vital function in maintaining the necessary environment for brain function but is an inconvenient obstacle to brain-directed therapeutics. Two papers published in this issue of Nature report the involvement of Mfsd2a, a member of the major facilitator superfamily regarded previously as an orphan transporter, in two aspects of blood–brain barrier function. David Silver and colleagues identify Mfsd2a as the major transporter for uptake of the omega fatty acid docosahexaenoic acid (DHA) into the brain. Mfsd2a is exclusively expressed in the endothelium of the blood–brain barrier, and Mfsd2a -knockout mice have reduced levels brain DHA, neuronal loss and reduced brain size and function. Chenghua Gu and colleagues find a role for Mfsd2 as a regulator of blood–brain barrier development and function: the barrier becomes 'leaky' in Mfsd2a-deficient mice, possibly a result of increased transcellular vesicular transport. 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) 1 , 2 , 3 . In concert with pericytes and astrocytes, this unique brain endothelial physiological barrier seals the CNS and controls substance influx and efflux 4 , 5 , 6 . 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 7 , 8 , 9 , 10 . 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