MSFD2A is critical for the formation and function of the blood brain barrier

By A. Ben-Zvi, Baptiste Lacoste, Esther Kur, Benjamin J. Andreone, Yoav Mayshar, Han Yan, Chenghua Gu. Nature, 2014

901 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Neurology, Oncology

View Paper: https://www.semanticscholar.org/paper/a09e6ec3d7a3bd1fd9fbe3aa24e437a39a6f70cd

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

In Neurology

In Oncology

Citations in the corpus

The blood–brain barrier in systemic infection and inflammation (2021, background): “One example is the major facilitator superfamily domain-containing 2a (Mfsd2a), gene, mutations in which cause a lethal microcephaly syndrome [127]; this gene codes for a docosahexaenoic acid transporter that suppresses caveolae-mediated transcytosis in microcerebrovascular endothelial cells [61].”
Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology (2017, background): “Although the mechanisms for DHA uptake into the brain had been enigmatic until recently, MFSD2A has been identified as the major transporter (52), as well as a negative regulator of transcytosis (53).”
Functional morphology of the blood-brain barrier in health and disease (2018, neutral): “Recently, a transporter of the major facilitator superfamily domain-containing (Mfsd) family, specifically Mfsd2a has been characterised as a transporter for the essential omega-3 fatty acid docosahexaenoic acid (DHA) in brain ECs that contribute to the regulation of vesicular traffic in CNS BBB/ BR”
The blood–brain barrier in health and disease: Important unanswered questions (2020, background): “However, barrier properties arise during development before astrogliogenesis takes place (Ben-Zvi et al., 2014; Daneman et al., 2010a; Sohet et al., 2015; Sauvageot and Stiles, 2002), delaying astrocytic contact with ECs does not affect barrier formation (Saunders et al., 2016), and laser ablation…”
The gut microbiota influences blood-brain barrier permeability in mice (2014, background): “This is similar to the Mfsd2adeficient mouse model in which leaky vessels are not associated with changes in the cerebrovascular network or pericyte abnormalities (11).”
A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity (2020, background): “This family of transporters may have dual function as recent studies showed its importance in maintaining BBB integrity as mice lacking MFSD2a show brain DHA deficits and compromised BBB [150, 151].”