Journal article
Tunicamycin-induced unfolded protein response in the developing mouse brain
Toxicology and applied pharmacology, Vol.283(3), pp.157-167
03/15/2015
DOI: 10.1016/j.taap.2014.12.019
PMCID: PMC4361256
PMID: 25620058
Abstract
Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress, resulting in the activation of the unfolded protein response (UPR). ER stress and UPR are associated with many neurodevelopmental and neurodegenerative disorders. The developing brain is particularly susceptible to environmental insults which may cause ER stress. We evaluated the UPR in the brain of postnatal mice. Tunicamycin, a commonly used ER stress inducer, was administered subcutaneously to mice of postnatal days (PDs) 4, 12 and 25. Tunicamycin caused UPR in the cerebral cortex, hippocampus and cerebellum of mice of PD4 and PD12, which was evident by the upregulation of ATF6, XBP1s, p-eIF2α, GRP78, GRP94 and MANF, but failed to induce UPR in the brain of PD25 mice. Tunicamycin-induced UPR in the liver was observed at all stages. In PD4 mice, tunicamycin-induced caspase-3 activation was observed in layer II of the parietal and optical cortex, CA1–CA3 and the subiculum of the hippocampus, the cerebellar external germinal layer and the superior/inferior colliculus. Tunicamycin-induced caspase-3 activation was also shown on PD12 but to a much lesser degree and mainly located in the dentate gyrus of the hippocampus, deep cerebellar nuclei and pons. Tunicamycin did not activate caspase-3 in the brain of PD25 mice and the liver of all stages. Similarly, immature cerebellar neurons were sensitive to tunicamycin-induced cell death in culture, but became resistant as they matured in vitro. These results suggest that the UPR is developmentally regulated and the immature brain is more susceptible to ER stress.
•Tunicamycin caused a development-dependent UPR in the mouse brain.•Immature brain was more susceptible to tunicamycin-induced endoplasmic reticulum stress.•Tunicamycin caused more neuronal death in immature brain than mature brain.•Tunicamycin-induced neuronal death is region-specific.
Details
- Title: Subtitle
- Tunicamycin-induced unfolded protein response in the developing mouse brain
- Creators
- Haiping Wang - University of KentuckyXin Wang - University of KentuckyZun-Ji Ke - Shanghai University of Traditional Chinese MedicineAshley L Comer - University of KentuckyMei Xu - University of KentuckyJacqueline A Frank - University of KentuckyZhuo Zhang - University of KentuckyXianglin Shi - University of KentuckyJia Luo - University of Kentucky
- Resource Type
- Journal article
- Publication Details
- Toxicology and applied pharmacology, Vol.283(3), pp.157-167
- DOI
- 10.1016/j.taap.2014.12.019
- PMID
- 25620058
- PMCID
- PMC4361256
- NLM abbreviation
- Toxicol Appl Pharmacol
- ISSN
- 0041-008X
- eISSN
- 1096-0333
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health (NIH), award: AA015407-09; DOI: 10.13039/501100001809, name: National Natural and Science Foundation of China, award: 81100247; name: Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, award: BX001721
- Language
- English
- Date published
- 03/15/2015
- Academic Unit
- Pathology
- Record Identifier
- 9984201254202771
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