Journal article 706 views 82 downloads
Orphan cytochrome P450 20a1 CRISPR/Cas9 mutants and neurobehavioral phenotypes in zebrafish
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Jared V. Goldstone,
John J. Stegeman
Scientific Reports, Volume: 11, Issue: 1, Start page: 23892
Swansea University Author:
David Lamb
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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...
| Published in: | Scientific Reports |
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| ISSN: | 2045-2322 |
| Published: |
Springer Science and Business Media LLC
2021
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa62080 |
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| 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 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. |
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| Keywords: |
Neurological disorders, Behavioural methods, Genetic engineering, Enzymes |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
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. |
| Issue: |
1 |
| Start Page: |
23892 |