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dc.contributor.authorTuschl, Karin
dc.contributor.authorWhite, Richard J
dc.contributor.authorTrivedi, Chintan
dc.contributor.authorValdivia, Leonardo E
dc.contributor.authorNiklaus, Stephanie
dc.contributor.authorBianco, Isaac H
dc.contributor.authorDadswell, Chris
dc.contributor.authorGonzález-Méndez, Ramón
dc.contributor.authorSealy, Ian M
dc.contributor.authorNeuhauss, Stephan CF
dc.contributor.authorHouart, Corinne
dc.contributor.authorRihel, Jason
dc.contributor.authorWilson, Stephen W
dc.contributor.authorBusch-Nentwich, Elisabeth M
dc.date.accessioned2022-06-29T19:49:43Z
dc.date.available2022-06-29T19:49:43Z
dc.date.issued2022-06-01
dc.date.submitted2020-02-23
dc.identifier.issn1754-8403
dc.identifier.otherdmm044594
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338593
dc.descriptionFunder: Academy of Medical Sciences; Id: http://dx.doi.org/10.13039/501100000691
dc.descriptionFunder: National Institute for Health Research; Id: http://dx.doi.org/10.13039/501100000272
dc.descriptionFunder: University College London; Id: http://dx.doi.org/10.13039/501100000765
dc.descriptionFunder: Neuroscience Center Zurich, University of Zurich
dc.descriptionFunder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100007155
dc.descriptionFunder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100010269
dc.description.abstractManganese neurotoxicity is a hallmark of hypermanganesemia with dystonia 2, an inherited manganese transporter defect caused by mutations in SLC39A14. To identify novel potential targets of manganese neurotoxicity, we performed transcriptome analysis of slc39a14-/- mutant zebrafish that were exposed to MnCl2. Differentially expressed genes mapped to the central nervous system and eye, and pathway analysis suggested that Ca2+ dyshomeostasis and activation of the unfolded protein response are key features of manganese neurotoxicity. Consistent with this interpretation, MnCl2 exposure led to decreased whole-animal Ca2+ levels, locomotor defects and changes in neuronal activity within the telencephalon and optic tectum. In accordance with reduced tectal activity, slc39a14-/- zebrafish showed changes in visual phototransduction gene expression, absence of visual background adaptation and a diminished optokinetic reflex. Finally, numerous differentially expressed genes in mutant larvae normalised upon MnCl2 treatment indicating that, in addition to neurotoxicity, manganese deficiency is present either subcellularly or in specific cells or tissues. Overall, we assembled a comprehensive set of genes that mediate manganese-systemic responses and found a highly correlated and modulated network associated with Ca2+ dyshomeostasis and cellular stress. This article has an associated First Person interview with the first author of the paper.
dc.languageen
dc.publisherThe Company of Biologists
dc.subjectZebrafish as a disease model
dc.subjectRESEARCH ARTICLE
dc.subjectZebrafish
dc.subjectSlc39a14
dc.subjectManganese
dc.subjectCalcium
dc.subjectTranscriptome
dc.titleLoss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish.
dc.typeArticle
dc.date.updated2022-06-29T19:49:42Z
prism.issueIdentifier6
prism.publicationNameDis Model Mech
prism.volume15
dc.identifier.doi10.17863/CAM.86006
dcterms.dateAccepted2022-04-25
rioxxterms.versionofrecord10.1242/dmm.044594
rioxxterms.versionAO
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0
dc.contributor.orcidTuschl, Karin [0000-0001-8599-8516]
dc.contributor.orcidBianco, Isaac H [0000-0002-3149-4862]
dc.contributor.orcidNeuhauss, Stephan CF [0000-0002-9615-480X]
dc.contributor.orcidBusch-Nentwich, Elisabeth M [0000-0001-6450-744X]
dc.identifier.eissn1754-8411
pubs.funder-project-idAction Medical Research (GN1999)
pubs.funder-project-idGreat Ormond Street Hospital Charity (V0018)
pubs.funder-project-idMedical Research Council (MR/V006754/1, MR/T020164/1, MR/L003775/1)
pubs.funder-project-idFondo Nacional de Desarrollo Científico y Tecnológico (11160951)
pubs.funder-project-idComisión Nacional de Investigación Científica y Tecnológica (REDI170300, REDES170010)
pubs.funder-project-idUniversidad Mayor (PEP I-2019074)
pubs.funder-project-idWellcome Trust (104682/Z/14/Z, 217150/Z/19/Z)
pubs.funder-project-idSchweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_173083)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/T001844/1)
pubs.funder-project-idWellcome Sanger Institute (WT098051, 206194)
cam.issuedOnline2022-06-15


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