Valproic acid, a histone deacetylase inhibitor, regulates cell proliferation in the adult zebrafish optic tectum

Dozawa, M., Kono, H., Sato, Y., Ito, Y., Tanaka, H., Ohshima, T.
Developmental dynamics : an official publication of the American Association of Anatomists   243(11): 1401-15 (Journal)
Registered Authors
Ohshima, Toshio, Sato, Yuki, Tanaka, Hideomi
HDAC, VPA, adult neurogenesis, optic tectum, zebrafish
MeSH Terms
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors/metabolism
  • Blotting, Western
  • Bromodeoxyuridine
  • Cell Cycle/drug effects
  • Cell Cycle/physiology
  • Cell Proliferation/drug effects*
  • Cell Proliferation/physiology
  • DNA Primers/genetics
  • Gene Expression Regulation/drug effects
  • Histone Deacetylase Inhibitors/pharmacology*
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • In Situ Nick-End Labeling
  • Neural Stem Cells/drug effects*
  • Real-Time Polymerase Chain Reaction
  • Receptors, Notch/metabolism
  • Signal Transduction/drug effects
  • Superior Colliculi/cytology*
  • Superior Colliculi/drug effects
  • Valproic Acid/pharmacology*
  • Zebrafish/metabolism
  • Zebrafish/physiology*
  • Zebrafish Proteins/metabolism
25091230 Full text @ Dev. Dyn.
Background: Valproic acid (VPA) has been used to treat epilepsy and bipolar disorder. Several reports have demonstrated that VPA functions as a histone deacetylase (HDAC) inhibitor. While VPA is known to cause teratogenic changes in the embryonic zebrafish brain, its effects on neural stem cells (NSCs) in both the embryonic and adult zebrafish are not well understood. Results: In this study, we observed a proliferative effect of VPA on NSCs in the embryonic hindbrain. In contrast, VPA reduced cell proliferation in the adult zebrafish optic tectum. Treatment with HDAC inhibitors showed a similar inhibitory effect on cell proliferation in the adult zebrafish optic tectum, suggesting that VPA reduces cell proliferation through HDAC inhibition. Cell cycle progression was also suppressed in the optic tectum of the adult zebrafish brain because of HDAC inhibition. Recent studies have demonstrated that HDAC inhibits the Notch signaling pathway; hence, adult zebrafish were treated with a Notch inhibitor. This increased the number of proliferating cells in the adult zebrafish optic tectum with down regulated expression of her4, a target of Notch signaling. Conclusions: These results suggest that VPA inhibits HDAC activity and upregulates Notch signaling to reduce cell proliferation in the optic tectum of adult zebrafish.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes