PUBLICATION
Exosc2 deficiency leads to developmental disorders by causing a nucleotide pool imbalance in zebrafish
- Authors
- Yatsuka, H., Hada, K., Shiraishi, H., Umeda, R., Morisaki, I., Urushibata, H., Shimizu, N., Sebastian, W.A., Hikida, T., Ishitani, T., Hanada, R., Shimada, T., Kimoto, K., Kubota, T., Hanada, T.
- ID
- ZDB-PUB-201219-1
- Date
- 2020
- Source
- Biochemical and Biophysical Research Communications 533: 1470-1476 (Journal)
- Registered Authors
- Hanada, Reiko, Hanada, Toshikatsu
- Keywords
- Exosc2, Neuronal defects, Nucleotide pool imbalance, Zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- CRISPR-Cas Systems
- Embryo, Nonmammalian/abnormalities
- Gene Expression Regulation, Developmental
- Gene Knockout Techniques
- Larva/genetics
- Larva/physiology
- Motor Neurons/drug effects
- Motor Neurons/pathology
- Myelin Basic Protein/genetics
- Nucleotides/genetics
- Nucleotides/metabolism*
- Sirolimus/pharmacology
- Zebrafish/embryology
- Zebrafish/genetics*
- PubMed
- 33333712 Full text @ Biochem. Biophys. Res. Commun.
Citation
Yatsuka, H., Hada, K., Shiraishi, H., Umeda, R., Morisaki, I., Urushibata, H., Shimizu, N., Sebastian, W.A., Hikida, T., Ishitani, T., Hanada, R., Shimada, T., Kimoto, K., Kubota, T., Hanada, T. (2020) Exosc2 deficiency leads to developmental disorders by causing a nucleotide pool imbalance in zebrafish. Biochemical and Biophysical Research Communications. 533:1470-1476.
Abstract
Exosc2 is one of the components of the exosome complex involved in RNA 3' end processing and degradation of various RNAs. Recently, EXOSC2 mutation has been reported in German families presenting short stature, hearing loss, retinitis pigmentosa, and premature aging. However, the in vivo function of EXOSC2 has been elusive. Herein, we generated Exosc2 knockout (exosc2-/-) zebrafish that showed larval lethality 13 days post fertilization, with microcephaly, loss of spinal motor neurons, myelin deficiency, and retinitis pigmentosa. Mechanistically, Exosc2 deficiency caused impaired mRNA turnover, resulting in a nucleotide pool imbalance. Rapamycin, which modulated mRNA turnover by inhibiting the mTOR pathway, improved nucleotide pool imbalance in exosc2-/- zebrafish, resulting in prolonged survival and partial rescue of neuronal defects. Taken together, our findings offer new insights into the disease pathogenesis caused by Exosc2 deficiency, and might help explain fundamental molecular mechanisms in neuronal diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, and spinal muscular atrophy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping