Editors' ChoiceNeurodevelopment

Filtering more than light in the developing retina

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Science Translational Medicine  19 Apr 2017:
Vol. 9, Issue 386, eaan2782
DOI: 10.1126/scitranslmed.aan2782

Abstract

Restricting transcytosis is essential for blood-retinal barrier formation.

Blood-central nervous system (CNS) barriers provide a security system for the CNS, selectively allowing certain factors to diffuse across, while blocking unwanted entry of others. Two key features critical to an intact barrier are (i) tight junctions joining adjacent cells, thereby preventing access between barrier cells, and (ii) controlled transcytosis, a process of vesicle trafficking of larger molecules through a barrier cell from blood to brain. However, the development of tight junctions and the mechanisms regulating transcytosis across barrier cells have remained a mystery. Chow and Gu now demonstrate that the formation of a functional blood-retinal barrier (BRB) hinges on developmentally regulated suppression of transcytosis in maturing endothelial cells. Tight junctions, in contrast, are formed as soon as vessels enter the CNS. These findings provide important insight into conditions where compromised barrier integrity may drive or exacerbate developmental disorders.

In this study, the group characterized the contributions of tight junctions and transcytosis in the relatively simple vascular structure of the BRB. In mouse, endothelial cells enter the retina soon after birth, and the vascular network is formed just after the first postnatal week. Initial transcardial injections of fluorescent tracers allowed spatiotemporal mapping of the functional BRB by postnatal day (P)10. Unexpectedly, electron microscopic analyses revealed that although numerous tracer-filled vesicles were observed in endothelial cells at P1, tight junctions already effectively sealed off space between adjacent cells, implying that unrestrained transcytosis was actually the culprit for the leaky barrier at early ages. Armed with this knowledge, the authors looked to Mfsd2a, an endothelial transport protein that regulates transcytosis in the blood-brain barrier. BRB maturation matched the onset of Mfsd2a expression in endothelial cells, and BRB transcytosis was suppressed in an Mfsd2a-dependent manner. Last, suppression of transcytosis in mice lacking caveolar vesicles (Caveolin-1-knockouts) prematurely formed a restrictive BRB that was not permissive to transport of typical cargo (e.g., bovine serum albumin). Collectively, these findings highlight developmentally regulated transcytosis as a key element defining the integrity of the BRB. Further, as these barriers pose significant therapeutic challenges to modern pharmaceuticals, these findings may help guide new strategies for manipulating transcytosis to facilitate specific drug delivery into the CNS.

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