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

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 luminal surface of endothelial cells. The zebrafish P-gp homolog Abcb4 is expressed at t...

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Autores principales: Thomas, Joanna R., Frye, William J. E., Robey, Robert W., Warner, Andrew C., Butcher, Donna, Matta, Jennifer L., Morgan, Tamara C., Edmondson, Elijah F., Gottesman, Michael M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10327217/
https://www.ncbi.nlm.nih.gov/pubmed/37425689
http://dx.doi.org/10.1101/2023.05.18.539313
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author Thomas, Joanna R.
Frye, William J. E.
Robey, Robert W.
Warner, Andrew C.
Butcher, Donna
Matta, Jennifer L.
Morgan, Tamara C.
Edmondson, Elijah F.
Gottesman, Michael M.
author_facet Thomas, Joanna R.
Frye, William J. E.
Robey, Robert W.
Warner, Andrew C.
Butcher, Donna
Matta, Jennifer L.
Morgan, Tamara C.
Edmondson, Elijah F.
Gottesman, Michael M.
author_sort Thomas, Joanna R.
collection PubMed
description 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 luminal surface of endothelial cells. The zebrafish P-gp homolog Abcb4 is expressed at the BBB and phenocopies 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. We found Abcg2a had the greatest substrate overlap with ABCG2, and Abcg2d appeared to be the least functionally similar. Using RNAscope in situ hybridization 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 studying the role of ABCG2 at the BBB.
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spelling pubmed-103272172023-07-08 Abcg2a is the functional homolog of human ABCG2 expressed at the zebrafish blood-brain barrier Thomas, Joanna R. Frye, William J. E. Robey, Robert W. Warner, Andrew C. Butcher, Donna Matta, Jennifer L. Morgan, Tamara C. Edmondson, Elijah F. Gottesman, Michael M. bioRxiv Article 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 luminal surface of endothelial cells. The zebrafish P-gp homolog Abcb4 is expressed at the BBB and phenocopies 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. We found Abcg2a had the greatest substrate overlap with ABCG2, and Abcg2d appeared to be the least functionally similar. Using RNAscope in situ hybridization 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 studying the role of ABCG2 at the BBB. Cold Spring Harbor Laboratory 2023-05-18 /pmc/articles/PMC10327217/ /pubmed/37425689 http://dx.doi.org/10.1101/2023.05.18.539313 Text en https://creativecommons.org/publicdomain/zero/1.0/This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license (https://creativecommons.org/publicdomain/zero/1.0/) .
spellingShingle Article
Thomas, Joanna R.
Frye, William J. E.
Robey, Robert W.
Warner, Andrew C.
Butcher, Donna
Matta, Jennifer L.
Morgan, Tamara C.
Edmondson, Elijah F.
Gottesman, Michael M.
Abcg2a is the functional homolog of human ABCG2 expressed at the zebrafish blood-brain barrier
title Abcg2a is the functional homolog of human ABCG2 expressed at the zebrafish blood-brain barrier
title_full Abcg2a is the functional homolog of human ABCG2 expressed at the zebrafish blood-brain barrier
title_fullStr Abcg2a is the functional homolog of human ABCG2 expressed at the zebrafish blood-brain barrier
title_full_unstemmed Abcg2a is the functional homolog of human ABCG2 expressed at the zebrafish blood-brain barrier
title_short Abcg2a is the functional homolog of human ABCG2 expressed at the zebrafish blood-brain barrier
title_sort abcg2a is the functional homolog of human abcg2 expressed at the zebrafish blood-brain barrier
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10327217/
https://www.ncbi.nlm.nih.gov/pubmed/37425689
http://dx.doi.org/10.1101/2023.05.18.539313
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