Induction of superficial cortical layer neurons from mouse embryonic stem cells by valproic acid

Neurosci Res. 2012 Jan;72(1):23-31. doi: 10.1016/j.neures.2011.09.012. Epub 2011 Oct 6.


Within the developing mammalian cortex, neural progenitors first generate deep-layer neurons and subsequently more superficial-layer neurons, in an inside-out manner. It has been reported recently that mouse embryonic stem cells (mESCs) can, to some extent, recapitulate cortical development in vitro, with the sequential appearance of neurogenesis markers resembling that in the developing cortex. However, mESCs can only recapitulate early corticogenesis; superficial-layer neurons, which are normally produced in later developmental periods in vivo, are under-represented. This failure of mESCs to reproduce later corticogenesis in vitro implies the existence of crucial factor(s) that are absent or uninduced in existing culture systems. Here we show that mESCs can give rise to superficial-layer neurons efficiently when treated with valproic acid (VPA), a histone deacetylase inhibitor. VPA treatment increased the production of Cux1-positive superficial-layer neurons, and decreased that of Ctip2-positive deep-layer neurons. These results shed new light on the mechanisms of later corticogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Line
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology*
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / drug effects*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Mice
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / physiology
  • Neurogenesis / drug effects*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology
  • Time Factors
  • Valproic Acid / pharmacology*


  • Histone Deacetylase Inhibitors
  • Valproic Acid