Suppression of transcytosis regulates zebrafish blood-brain barrier function

Abstract
Data availability
Article and author information
Metrics

Abstract

As an optically transparent model organism with an endothelial blood-brain barrier (BBB), zebrafish offer a powerful tool to study the vertebrate BBB. However, the precise developmental profile of functional zebrafish BBB acquisition and the subcellular and molecular mechanisms governing the zebrafish BBB remain poorly characterized. Here we capture the dynamics of developmental BBB leakage using live imaging, revealing a combination of steady accumulation in the parenchyma and sporadic bursts of tracer leakage. Electron microscopy studies further reveal high levels of transcytosis in brain endothelium early in development that are suppressed later. The timing of this suppression of transcytosis coincides with the establishment of BBB function. Finally, we demonstrate a key mammalian BBB regulator Mfsd2a, which inhibits transcytosis, plays a conserved role in zebrafish, as mfsd2aa mutants display increased BBB permeability due to increased transcytosis. Our findings indicate a conserved developmental program of barrier acquisition between zebrafish and mice.

Data availability

All raw data is attached as an excel spreadsheet.

Article and author information

Author details

Natasha M O'Brown

Department of Neurobiology, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0718-7037
Sean G Megason

Department of Systems Biology, Harvard Medical School, Boston, United States

For correspondence
Sean_Megason@hms.harvard.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9330-2934
Chenghua Gu

Department of Neurobiology, Harvard Medical School, Boston, United States

For correspondence
Chenghua_Gu@hms.harvard.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4212-7232

Funding

Damon Runyon Cancer Research Foundation (Postdoctoral Research Fellowship)

Natasha M O'Brown

Fidelity Biosciences

Chenghua Gu

NIH Director's Pioneer Award (NIH DP1 NS092473)

Chenghua Gu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the NIH. All animals were handled according to approved institutional animal care and use committee (IACUC) protocols (protocol 04487) of Harvard Medical School. All work was approved by the Harvard Medical Area Standing Committee on Animals.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.