Gradual Suppression of Transcytosis Governs Functional Blood-Retinal Barrier Formation

• Published in: Neuron (Cambridge, Mass.) Vol. 93; no. 6; pp. 1325 - 1333.e3
• Main Authors: Chow, Brian Wai, Gu, Chenghua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.03.2017; Elsevier Limited
• Subjects: Adults; Age; Angiogenesis; Animals; Biotin; Blood circulation; Blood vessels; Blood-brain barrier; blood-CNS barrier; blood-retinal barrier; Blood-Retinal Barrier - growth & development; Blood-Retinal Barrier - ultrastructure; Catenin; Cav-1; Caveolin 1 - genetics; Caveolin 1 - physiology; Central nervous system; Chimeras; Dextran; Drug delivery; Endothelial cells; Endothelial Cells - physiology; Female; Glia; Hypoxia; Male; Membrane Transport Proteins - biosynthesis; Membrane Transport Proteins - genetics; Membrane Transport Proteins - physiology; Mfsd2a; Mice; Mice, Knockout; Nervous system; Neurodegeneration; Neurodegenerative diseases; Neuroglia; Optic nerve; pericytes; Permeability; Phototransduction; Retina; retinal vasculature; Spinal cord; Tight junctions; Tight Junctions - genetics; Tight Junctions - physiology; Tracers; transcytosis; Transcytosis - genetics; Transcytosis - physiology; Transplantation; Vascular endothelial growth factor; blood-CNS barrier; blood-brain barrier; Mfsd2a; Cav-1; blood-retinal barrier; endothelial cells; pericytes; transcytosis; tight junctions; retinal vasculature
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2017.02.043

Blood-central nervous system (CNS) barriers partition neural tissues from the blood, providing a homeostatic environment for proper neural function. The endothelial cells that form blood-CNS barriers have specialized tight junctions and low rates of transcytosis to limit the flux of substances between blood and CNS. However, the relative contributions of these properties to CNS barrier permeability are unknown. Here, by studying functional blood-retinal barrier (BRB) formation in mice, we found that immature vessel leakage occurs entirely through transcytosis, as specialized tight junctions are functional as early as vessel entry into the CNS. A functional barrier forms only when transcytosis is gradually suppressed during development. Mutant mice with elevated or reduced levels of transcytosis have delayed or precocious sealing of the BRB, respectively. Therefore, the temporal regulation of transcytosis governs the development of a functional BRB, and suppression of transcytosis is a principal contributor for functional barrier formation. •Retinal vessels at P1 have functional tight junctions but display bulk transcytosis•Immature vessel leakage is entirely due to transcytosis and not via tight junctions•Gradual suppression of transcytosis governs functional blood-retinal barrier formation•Retinal vasculature is a tractable system to study CNS barriers Chow and Gu characterized the spatio-temporal development of functional blood-retinal barrier formation and demonstrated that immature vessel leakage is entirely due to bulk transcytosis and not via tight junctions. Gradual suppression of transcytosis determines functional blood-retinal barrier formation.