Aberrant neuronal differentiation and inhibition of dendrite outgrowth resulting from endoplasmic reticulum stress

J Neurosci Res. 2014 Sep;92(9):1122-33. doi: 10.1002/jnr.23389. Epub 2014 Apr 10.


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.

Keywords: endoplasmic reticulum stress; neurite outgrowth; neuronal differentiation; ubiquitin ligase HRD1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites / pharmacology
  • Carcinoma / pathology
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Line, Tumor
  • Dendrites / drug effects
  • Dendrites / physiology*
  • Deoxyglucose / pharmacology
  • Doublecortin Domain Proteins
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / physiology*
  • Glial Fibrillary Acidic Protein / metabolism
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Neurons / cytology*
  • Neurons / drug effects
  • Neuropeptides / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Peptide / metabolism
  • Transcription Factor CHOP / metabolism
  • Tretinoin / pharmacology
  • Tunicamycin / pharmacology
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*


  • Antimetabolites
  • Doublecortin Domain Proteins
  • GRP78 protein, rat
  • Glial Fibrillary Acidic Protein
  • Heat-Shock Proteins
  • KDEL receptor
  • Microtubule-Associated Proteins
  • Neuropeptides
  • RNA, Messenger
  • Receptors, Peptide
  • Tunicamycin
  • Transcription Factor CHOP
  • Tretinoin
  • Deoxyglucose
  • Ubiquitin-Protein Ligases