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