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

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. 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 efflux4,5,6. 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 CNS7,8,9,10. 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 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.