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.
Citation
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. (2022) Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish. Disease models & mechanisms. 15(6).
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping