Suppression of transcytosis regulates zebrafish blood-brain barrier function

  1. Natasha M O'Brown
  2. Sean G Megason  Is a corresponding author
  3. Chenghua Gu  Is a corresponding author
  1. Harvard Medical School, United States

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.

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All raw data is attached as an excel spreadsheet.

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Author details

  1. Natasha M O'Brown

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0718-7037
  2. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9330-2934
  3. 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.
    ORCID icon "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.

Reviewing Editor

  1. Richard Daneman, University of California - San Diego, United States

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.

Version history

  1. Received: April 2, 2019
  2. Accepted: August 19, 2019
  3. Accepted Manuscript published: August 20, 2019 (version 1)
  4. Version of Record published: September 4, 2019 (version 2)

Copyright

© 2019, O'Brown et al.

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.

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  1. Natasha M O'Brown
  2. Sean G Megason
  3. Chenghua Gu
(2019)
Suppression of transcytosis regulates zebrafish blood-brain barrier function
eLife 8:e47326.
https://doi.org/10.7554/eLife.47326

Share this article

https://doi.org/10.7554/eLife.47326

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