Journal
JOURNAL OF NEUROSCIENCE
Volume 36, Issue 42, Pages 10908-10919Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0229-16.2016
Keywords
deacetylation; histone; neocortex; neural progenitor cell; neuronogenesis
Categories
Funding
- Japan Society for the Promotion of Science [B: 20390299, 23390276, 26293248, C: 25461560, B: 22791001, 22791038]
- Mother and Child Health Foundation
- Japan Epilepsy Research Foundation
- Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research
- Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics
- Japan Foundation for Pediatric Research Grant
- Grants-in-Aid for Scientific Research [26462714, 26293248, 22791038, 23390276] Funding Source: KAKEN
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Valproic acid (VPA), a widely used antiepileptic drug, is an inhibitor of histone deacetylases, which epigenetically modify cell proliferation/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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