Aberrant neuronal differentiation and inhibition of dendrite outgrowth resulting from endoplasmic reticulum stress
Article first published online: 10 APR 2014
© 2014 The Authors Journal of Neuroscience Research Published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Journal of Neuroscience Research
Volume 92, Issue 9, pages 1122–1133, September 2014
How to Cite
Kawada, K., Iekumo, T., Saito, R., Kaneko, M., Mimori, S., Nomura, Y. and Okuma, Y. (2014), Aberrant neuronal differentiation and inhibition of dendrite outgrowth resulting from endoplasmic reticulum stress. J. Neurosci. Res., 92: 1122–1133. doi: 10.1002/jnr.23389
- Issue published online: 12 JUL 2014
- Article first published online: 10 APR 2014
- Manuscript Accepted: 5 MAR 2014
- Manuscript Revised: 23 FEB 2014
- Manuscript Received: 17 OCT 2013
- Japan Society for the Promotion of Science (JSPS) KAKENHI. Grant Numbers: 24790085, 21590101, 24590119, 21300142, 22020032
- ubiquitin ligase HRD1;
- endoplasmic reticulum stress;
- neuronal differentiation;
- neurite outgrowth
Neural stem cells (NSCs) play an essential role in development of the central nervous system. Endoplasmic reticulum (ER) stress induces neuronal death. After neuronal death, neurogenesis is generally enhanced to repair the damaged regions. However, it is unclear whether ER stress directly affects neurogenesis-related processes such as neuronal differentiation and dendrite outgrowth. We evaluated whether neuronal differentiation and dendrite outgrowth were regulated by HRD1, a ubiquitin ligase that was induced under mild conditions of tunicamycin-induced ER stress. Neurons were differentiated from mouse embryonic carcinoma P19 cells by using retinoic acid. The differentiated cells were cultured for 8 days with or without tunicamycin and HRD1 knockdown. The ER stressor led to markedly increased levels of ER stress. ER stress increased the expression levels of neuronal marker βIII-tubulin in 8-day-differentiated cells. However, the neurites of dendrite marker microtubule-associated protein-2 (MAP-2)-positive cells appeared to retract in response to ER stress. Moreover, ER stress markedly reduced the dendrite length and MAP-2 expression levels, whereas it did not affect the number of surviving mature neurons. In contrast, HRD1 knockdown abolished the changes in expression of proteins such as βIII-tubulin and MAP-2. These results suggested that ER stress caused aberrant neuronal differentiation from NSCs followed by the inhibition of neurite outgrowth. These events may be mediated by increased HRD1 expression. © 2014 The Authors Journal of Neuroscience Research Published by Wiley Periodicals, Inc.