@article{fedb014f265447aa9698ae41cfc50c71,
title = "Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish",
abstract = "Manganese 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 manganesesystemic 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. ",
keywords = "Calcium, Manganese, Slc39a14, Transcriptome, Zebrafish",
author = "Karin Tuschl and White, {Richard J.} and Chintan Trivedi and Valdivia, {Leonardo E.} and Stephanie Niklaus and Bianco, {Isaac H.} and Chris Dadswell and Ram{\'o}n Gonz{\'a}lez-M{\'e}ndez and Sealy, {Ian M.} and Neuhauss, {Stephan C.F.} and Corinne Houart and Jason Rihel and Wilson, {Stephen W.} and Busch-Nentwich, {Elisabeth M.}",
note = "Funding Information: K.T. was supported by Action Medical Research (GN1999), the Academy of Medical Sciences, the National Institute for Health Research (NIHR, Academic Clinical Lectureship), the Great Ormond Street Hospital Charity (V0018) and the Medical Research Council (MR/V006754/1). K.T., S.C.F.N and S.W.W. were supported by the University College London and the Neuroscience Center Zurich, University of Zurich Collaboration. L.E.V. was funded by the Fondo Nacional de Desarrollo Cientı{\'f} ico y Tecnol{\'o}gico (FONDECYT) grant (11160951), Comisi{\'o}n Nacional de Investigaci{\'o}n Cientı{\'f} ica y Tecnol{\'o}gica (CONICYT) International network grants (REDI170300 and REDES170010), and Universidad Mayor FDP grant (PEP I-2019074). C.T., L.E.V. and S.W.W. were supported by Medical Research Council grants (MR/L003775/1 and MR/T020164/1) and a Wellcome Trust investigator award (104682/Z/14/Z). S.C.F.N. was supported by the Schweizerischer Nationalfonds zur F{\"o}rderung der Wissenschaftlichen Forschung (Swiss National Science Foundation; 31003A_173083) J.R. was supported by the Biotechnology and Biological Sciences Research Council (BBSRC; BB/T001844/1) and Wellcome Trust (217150/Z/19/Z). E.M.B.-N. was supported by core grants to the Wellcome Sanger Institute (WT098051 and 206194). This publication presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Open Access funding provided by the Wellcome Trust and UKRI. Deposited in PMC for immediate release. Publisher Copyright: {\textcopyright} 2022. Published by The Company of Biologists Ltd.",
year = "2022",
month = jun,
doi = "10.1242/dmm.044594",
language = "English",
volume = "15",
journal = "DMM Disease Models and Mechanisms",
issn = "1754-8403",
publisher = "The Company of Biologists",
number = "6",
}