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Abcg2a is the functional homolog of human ABCG2 expressed at the zebrafish blood-brain barrier.

Authors
  • Thomas, Joanna R1
  • Frye, William J E1
  • Robey, Robert W1
  • Warner, Andrew C2
  • Butcher, Donna2
  • Matta, Jennifer L2
  • Morgan, Tamara C2
  • Edmondson, Elijah F2
  • Salazar, Paula B1
  • Ambudkar, Suresh V1
  • Gottesman, Michael M1
  • 1 Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 2 Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Type
Published Article
Journal
bioRxiv : the preprint server for biology
Publication Date
Jan 08, 2024
Identifiers
DOI: 10.1101/2023.05.18.539313
PMID: 37425689
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

A principal protective component of the mammalian blood-brain barrier (BBB) is the high expression of the multidrug efflux transporters P-glycoprotein (P-gp, encoded by ABCB1) and ABCG2 (encoded by ABCG2) on the lumenal surface of endothelial cells. The zebrafish P-gp homolog Abcb4 is expressed at the BBB and phenocopies human P-gp. Comparatively little is known about the four zebrafish homologs of the human ABCG2 gene: abcg2a, abcg2b, abcg2c, and abcg2d. Here we report the functional characterization and brain tissue distribution of zebrafish ABCG2 homologs. To determine substrates of the transporters, we stably expressed each in HEK-293 cells and performed cytotoxicity and fluorescent efflux assays with known ABCG2 substrates. To assess the expression of transporter homologs, we used a combination of RNAscope in situ hybridization probes and immunohistochemistry to stain paraffin-embedded sections of adult and larval zebrafish. We found Abcg2a had the greatest substrate overlap with ABCG2, and Abcg2d appeared to be the least functionally similar. We identified abcg2a as the only homolog expressed at the adult and larval zebrafish BBB, based on its localization to claudin-5 positive brain vasculature. These results demonstrate the conserved function of zebrafish Abcg2a and suggest that zebrafish may be an appropriate model organism for the studying the role of ABCG2 at the BBB.

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