eprintid: 10148179
rev_number: 6
eprint_status: archive
userid: 699
dir: disk0/10/14/81/79
datestamp: 2022-05-10 12:43:43
lastmod: 2022-05-10 12:43:43
status_changed: 2022-05-10 12:43:43
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Tuschl, Karin
creators_name: White, Richard J
creators_name: Trivedi, Chintan
creators_name: Valdivia, Leonardo E
creators_name: Niklaus, Stephanie
creators_name: Bianco, Isaac H
creators_name: Dadswell, Chris
creators_name: González-Méndez, Ramón
creators_name: Sealy, Ian M
creators_name: Neuhauss, Stephan CF
creators_name: Houart, Corinne
creators_name: Rihel, Jason
creators_name: Wilson, Stephen W
creators_name: Busch-Nentwich, Elisabeth M
title: Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish
ispublished: inpress
divisions: C08
divisions: F96
divisions: B02
divisions: UCL
divisions: D09
divisions: G02
keywords: Calcium, Manganese, Transcriptome, Zebrafish, slc39a14
note: © 2022. Published by The Company of Biologists Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium
provided that the original work is properly attributed.
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 unexposed and exposed to MnCl2. Differentially expressed genes mapped to the central nervous system and eye, and pathway analysis suggested that calcium 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 calcium 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 calcium dyshomeostasis and cellular stress.
date: 2022-05-06
date_type: published
publisher: The Company of Biologists
official_url: https://doi.org/10.1242/dmm.044594
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1953471
doi: 10.1242/dmm.044594
medium: Print-Electronic
pii: 275312
lyricists_name: Wilson, Stephen
lyricists_name: Bianco, Isaac
lyricists_name: Rihel, Jason
lyricists_id: SWILS65
lyricists_id: IHBIA26
lyricists_id: JRIHE66
actors_name: Kalinowski, Damian
actors_id: DKALI47
actors_role: owner
funding_acknowledgements: MR/V006754/1 [Medical Research Council]; GN1999 [Action Medical Research]; 104682/Z/14/Z [Wellcome Trust]; 31003A_173083 [Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung]; BB/T001844/1 [Biotechnology and Biological Sciences Research Council]; REDI170300 [Comisin Nacional de Investigacin Cient-fica y Tecnologica]
full_text_status: public
publication: Disease Models and Mechanisms
event_location: England
issn: 1754-8403
citation:        Tuschl, Karin;    White, Richard J;    Trivedi, Chintan;    Valdivia, Leonardo E;    Niklaus, Stephanie;    Bianco, Isaac H;    Dadswell, Chris;                             ... Busch-Nentwich, Elisabeth M; + view all <#>        Tuschl, Karin;  White, Richard J;  Trivedi, Chintan;  Valdivia, Leonardo E;  Niklaus, Stephanie;  Bianco, Isaac H;  Dadswell, Chris;  González-Méndez, Ramón;  Sealy, Ian M;  Neuhauss, Stephan CF;  Houart, Corinne;  Rihel, Jason;  Wilson, Stephen W;  Busch-Nentwich, Elisabeth M;   - view fewer <#>    (2022)    Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish.                   Disease Models and Mechanisms        10.1242/dmm.044594 <https://doi.org/10.1242/dmm.044594>.    (In press).    Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10148179/1/Bianco_Loss%20of%20slc39a14%20causes%20simultaneous%20manganese%20hypersensitivity%20and%20deficiency%20in%20zebrafish_AAM.pdf