In utero exposure to valproic acid induces neocortical dysgenesis via dysregulation of neural progenitor cell proliferation/differentiation

Kimino Fujimura, Takayuki Mitsuhashi, Shinsuke Shibata, Sachiko Shimozato, Takao Takahashi

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Valproic acid (VPA), a widely used antiepileptic drug, is an inhibitor of histone deacetylases, which epigenetically modify cell prolifera-tion/differentiation in developing tissues. A series of recent clinical studies in humans reported that VPA exposure in utero impaired histogenesis and the development of the central nervous system, leading to increased risks of congenital malformation and the impairment of higher brain functions in children. In the present study conducted in mice, we report that VPA exposure in utero (1) increases the amount of acetylated histone proteins, (2) alters the expression of G1-phase regulatory proteins, (3) inhibits the cell cycle exit of neural progenitor cells during the early stage of neocortical histogenesis, and (4) increases the production of projection neurons distributed in the superficial neocortical layers in embryonic brains. Together, our findings show that VPA exposure in utero alters proliferation/differentiation characteristics of neural progenitor cells and hence leads to the neocortical dysgenesis.

Original languageEnglish
Pages (from-to)10908-10919
Number of pages12
JournalJournal of Neuroscience
Volume36
Issue number42
DOIs
Publication statusPublished - 2016 Oct 19

Fingerprint

Valproic Acid
Cell Differentiation
Stem Cells
Cell Proliferation
Histone Deacetylases
Brain
G1 Phase
Anticonvulsants
Histones
Cell Cycle
Proteins
Central Nervous System
Neurons

Keywords

  • Deacetylation
  • Histone
  • Neocortex
  • Neural progenitor cell
  • Neuronogenesis

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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abstract = "Valproic acid (VPA), a widely used antiepileptic drug, is an inhibitor of histone deacetylases, which epigenetically modify cell prolifera-tion/differentiation in developing tissues. A series of recent clinical studies in humans reported that VPA exposure in utero impaired histogenesis and the development of the central nervous system, leading to increased risks of congenital malformation and the impairment of higher brain functions in children. In the present study conducted in mice, we report that VPA exposure in utero (1) increases the amount of acetylated histone proteins, (2) alters the expression of G1-phase regulatory proteins, (3) inhibits the cell cycle exit of neural progenitor cells during the early stage of neocortical histogenesis, and (4) increases the production of projection neurons distributed in the superficial neocortical layers in embryonic brains. Together, our findings show that VPA exposure in utero alters proliferation/differentiation characteristics of neural progenitor cells and hence leads to the neocortical dysgenesis.",
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AU - Mitsuhashi, Takayuki

AU - Shibata, Shinsuke

AU - Shimozato, Sachiko

AU - Takahashi, Takao

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