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Orphan cytochrome P450 20a1 CRISPR/Cas9 mutants and neurobehavioral phenotypes in zebrafish

Nadja R. Brun, Matthew C. Salanga, Francisco X. Mora-Zamorano, David Lamb Orcid Logo, Jared V. Goldstone, John J. Stegeman

Scientific Reports, Volume: 11, Issue: 1, Start page: 23892

Swansea University Author: David Lamb Orcid Logo

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DOI (Published version): 10.1038/s41598-021-03068-3

Abstract

Orphan cytochrome P450 (CYP) enzymes are those for which biological substrates and function(s) are unknown. Cytochrome P450 20A1 (CYP20A1) is the last human orphan P450 enzyme, and orthologs occur as single genes in every vertebrate genome sequenced to date. The occurrence of high levels of CYP20A1...

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Published in: Scientific Reports
ISSN: 2045-2322
Published: Springer Science and Business Media LLC 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa62080
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spelling 2022-12-08T11:56:36.0683076 v2 62080 2022-11-29 Orphan cytochrome P450 20a1 CRISPR/Cas9 mutants and neurobehavioral phenotypes in zebrafish 1dc64e55c2c28d107ef7c3db984cccd2 0000-0001-5446-2997 David Lamb David Lamb true false 2022-11-29 BMS Orphan cytochrome P450 (CYP) enzymes are those for which biological substrates and function(s) are unknown. Cytochrome P450 20A1 (CYP20A1) is the last human orphan P450 enzyme, and orthologs occur as single genes in every vertebrate genome sequenced to date. The occurrence of high levels of CYP20A1 transcripts in human substantia nigra and hippocampus and abundant maternal transcripts in zebrafish eggs strongly suggest roles both in the brain and during early embryonic development. Patients with chromosome 2 microdeletions including CYP20A1 show hyperactivity and bouts of anxiety, among other conditions. Here, we created zebrafish cyp20a1 mutants using CRISPR/Cas9, providing vertebrate models with which to study the role of CYP20A1 in behavior and other neurodevelopmental functions. The homozygous cyp20a1 null mutants exhibited significant behavioral differences from wild-type zebrafish, both in larval and adult animals. Larval cyp20a1-/- mutants exhibited a strong increase in light-simulated movement (i.e., light-dark assay), which was interpreted as hyperactivity. Further, the larvae exhibited mild hypoactivity during the adaptation period of the optomotor assays. Adult cyp20a1 null fish showed a pronounced delay in adapting to new environments, which is consistent with an anxiety paradigm. Taken together with our earlier morpholino cyp20a1 knockdown results, the results described herein suggest that the orphan CYP20A1 has a neurophysiological role. Journal Article Scientific Reports 11 1 23892 Springer Science and Business Media LLC 2045-2322 Neurological disorders, Behavioural methods, Genetic engineering, Enzymes 13 12 2021 2021-12-13 10.1038/s41598-021-03068-3 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee These studies were supported in part by the Boston University Superfund Research Program NIH 5P42ES007381 (MCS, NRB, FXM, JVG, JJS), the Woods Hole Center for Oceans and Human Health (NIH: P01ES021923 and P01ES028938; NSF: OCE-1314642 and OCE-1840381; NRB and JJS), and EBI/EMBL Medakatox NIEHS R01ES029917 (JVG). DCL was funded by a UK-US Fulbright Scholarship. This paper is dedicated in memory of Dr. Michael Waterman. 2022-12-08T11:56:36.0683076 2022-11-29T10:11:11.7341841 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Nadja R. Brun 1 Matthew C. Salanga 2 Francisco X. Mora-Zamorano 3 David Lamb 0000-0001-5446-2997 4 Jared V. Goldstone 5 John J. Stegeman 6 62080__26034__41289743629341d886bd4a87b27e2eac.pdf 62080.pdf 2022-12-08T11:54:58.7601475 Output 3491221 application/pdf Version of Record true © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License true eng http://creativecommons.org/licenses/by/4.0/
title Orphan cytochrome P450 20a1 CRISPR/Cas9 mutants and neurobehavioral phenotypes in zebrafish
spellingShingle Orphan cytochrome P450 20a1 CRISPR/Cas9 mutants and neurobehavioral phenotypes in zebrafish
David Lamb
title_short Orphan cytochrome P450 20a1 CRISPR/Cas9 mutants and neurobehavioral phenotypes in zebrafish
title_full Orphan cytochrome P450 20a1 CRISPR/Cas9 mutants and neurobehavioral phenotypes in zebrafish
title_fullStr Orphan cytochrome P450 20a1 CRISPR/Cas9 mutants and neurobehavioral phenotypes in zebrafish
title_full_unstemmed Orphan cytochrome P450 20a1 CRISPR/Cas9 mutants and neurobehavioral phenotypes in zebrafish
title_sort Orphan cytochrome P450 20a1 CRISPR/Cas9 mutants and neurobehavioral phenotypes in zebrafish
author_id_str_mv 1dc64e55c2c28d107ef7c3db984cccd2
author_id_fullname_str_mv 1dc64e55c2c28d107ef7c3db984cccd2_***_David Lamb
author David Lamb
author2 Nadja R. Brun
Matthew C. Salanga
Francisco X. Mora-Zamorano
David Lamb
Jared V. Goldstone
John J. Stegeman
format Journal article
container_title Scientific Reports
container_volume 11
container_issue 1
container_start_page 23892
publishDate 2021
institution Swansea University
issn 2045-2322
doi_str_mv 10.1038/s41598-021-03068-3
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
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description Orphan cytochrome P450 (CYP) enzymes are those for which biological substrates and function(s) are unknown. Cytochrome P450 20A1 (CYP20A1) is the last human orphan P450 enzyme, and orthologs occur as single genes in every vertebrate genome sequenced to date. The occurrence of high levels of CYP20A1 transcripts in human substantia nigra and hippocampus and abundant maternal transcripts in zebrafish eggs strongly suggest roles both in the brain and during early embryonic development. Patients with chromosome 2 microdeletions including CYP20A1 show hyperactivity and bouts of anxiety, among other conditions. Here, we created zebrafish cyp20a1 mutants using CRISPR/Cas9, providing vertebrate models with which to study the role of CYP20A1 in behavior and other neurodevelopmental functions. The homozygous cyp20a1 null mutants exhibited significant behavioral differences from wild-type zebrafish, both in larval and adult animals. Larval cyp20a1-/- mutants exhibited a strong increase in light-simulated movement (i.e., light-dark assay), which was interpreted as hyperactivity. Further, the larvae exhibited mild hypoactivity during the adaptation period of the optomotor assays. Adult cyp20a1 null fish showed a pronounced delay in adapting to new environments, which is consistent with an anxiety paradigm. Taken together with our earlier morpholino cyp20a1 knockdown results, the results described herein suggest that the orphan CYP20A1 has a neurophysiological role.
published_date 2021-12-13T04:21:25Z
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