Histone Deacetylase 3 Governs Perinatal Cerebral Development via Neural Stem and Progenitor Cells

• Main Authors: Lin Li, Jianliang Jin, Xiang-Jiao Yang
• Format: Article
• Language: English
• Published: Elsevier 2019-10-01
• Series: iScience
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004219303530

Summary: We report that cerebrum-specific inactivation of the histone deacetylase 3 (HDAC3) gene causes striking developmental defects in the neocortex, hippocampus, and corpus callosum; post-weaning lethality; and abnormal behaviors, including hyperactivity and anxiety. The defects are due to rapid loss of embryonic neural stem and progenitor cells (NSPCs). Premature neurogenesis and abnormal neuronal migration in the mutant brain alter NSPC homeostasis. Mutant cerebral cortices also display augmented DNA damage responses, apoptosis, and histone hyperacetylation. Moreover, mutant NSPCs are impaired in forming neurospheres in vitro, and treatment with the HDAC3-specific inhibitor RGFP966 abolishes neurosphere formation. Transcriptomic analyses of neonatal cerebral cortices and cultured neurospheres support that HDAC3 regulates transcriptional programs through interaction with different transcription factors, including NFIB. These findings establish HDAC3 as a major deacetylase critical for perinatal development of the mouse cerebrum and NSPCs, thereby suggesting a direct link of this enzymatic epigenetic regulator to human cerebral and intellectual development. : Cellular Neuroscience; Developmental Neuroscience; Molecular Neuroscience; Neuroscience Subject Areas: Cellular Neuroscience, Developmental Neuroscience, Molecular Neuroscience, Neuroscience