PUBLICATION

Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish

Authors
Tuschl, K., White, R.J., Trivedi, C., Valdivia, L.E., Niklaus, S., Bianco, I.H., Dadswell, C., González-Méndez, R., Sealy, I.M., Neuhauss, S.C.F., Houart, C., Rihel, J., Wilson, S.W., Busch-Nentwich, E.M.
ID
ZDB-PUB-220507-4
Date
2022
Source
Disease models & mechanisms   15(6): (Journal)
Registered Authors
Bianco, Isaac, Busch-Nentwich, Elisabeth, Houart, Corinne, Neuhauss, Stephan, Rihel, Jason, Tuschl, Karin, Valdivia, Leonardo, Wilson, Steve
Keywords
Calcium, Manganese, Transcriptome, Zebrafish, slc39a14
MeSH Terms
  • Animals
  • Calcium/metabolism
  • Cation Transport Proteins*/genetics
  • Cation Transport Proteins*/metabolism
  • Dystonia*/genetics
  • Ions/metabolism
  • Manganese/metabolism
  • Manganese/toxicity
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed
35514229 Full text @ Dis. Model. Mech.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping