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

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)1–3. In concert with pericytes and astrocytes, this unique brain endothelial physiological barrier seals the CNS and controls substance influx and efflux4–6. 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 CNS7–10. 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 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.

Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood–brain barrier disruption after ischemic brain injury

“…Two important features of brain ECs, including the high sealing efficiency via paracellular junctions and relatively low transcytosis rate, help maintain the low permeability of the BBB to cerebrospinal fluid and blood components (35). Soon after I/R, there are increases in transcellular trafficking and paracellular permeability via MMP-independent mechanisms (8,9).…”

Microbiota and the control of blood-tissue barriers

“…40 Both barriers physically separate their respective organs into apical and basal compartments exerting strict control over the transfer of ions and molecules. The BTB develops postnatally in rodents and during puberty in humans, 19 while the BBB is formed prenatally in both rodents 6,7 and humans. 41 Both barriers create 'immune-privileged sites', i.e., tissue transplanted into the brain 42 or the interstitial space of the testis 39 is not rejected.…”

“…A functional BBB that excludes tracers administered intravenously from the CNS parenchyma is present between E15-E16. 6,7 Normally, astrocytes appear postnatally to provide additional support to the functional BBB during adulthood, as well as in connection with injury and disease (Fig. 2).…”

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

“…CNS vasculature undergoes angiogenesis and remodeling at early postnatal stages (19,20), alterations of which can affect subsequent BBB properties (2,21). To determine whether S1P 1 regulates the BBB directly or indirectly via vascular developmental defects (2, 21), we deleted endothelial S1pr1 in adult mice (>8 wk) and analyzed them for BBB function 4 wk after gene deletion.…”

“…S1C) from S1pr1 iECKO brain displayed normal mRNA expression of brain EC-specific genes (Slco1c1, Slc2a1, Abcb1a, Mfsd2a, and Zic3) (ref. 21; Fig. S1D) or other components of the NVU, smooth muscle cells (Acta2), pericytes (Pdgfrb), astrocytes (Gfap, Aqp4, and Mfge8), and perivascular macrophages (Mrc1 and Lyve1) (ref.…”