Regulation of Central Nervous System Development by Class I Histone Deacetylases

Abstract

Neurodevelopment is a highly complex process composed of several carefully regulated events starting from the proliferation of neuroepithelial cells and culminating with and refining of neural networks and synaptic transmission. Improper regulation of any of these neurodevelopmental events often results in severe brain dysfunction. Accumulating evidence indicates that epigenetic modifications of chromatin play a key role in neurodevelopmental regulation. Among these modifications are histone acetylation and deacetylation, which control access of transcription factors to DNA, thereby regulating gene transcription. Histone deacetylation, which restricts access of transcription factor repressing gene transcription, involves the action of members of a family of 18 enzymes, the histone deacetylases (HDAC), which are subdivided in 4 subgroups. This review focuses on the Group 1 HDACs - HDAC 1, 2, 3, and 8. Although much of the evidence for HDAC involvement in neurodevelopment has come from the use of pharmacological inhibitors, because these agents are generally nonselective with regard to their effects on individual members of the HDAC family, this review is limited to evidence garnered from the use of molecular genetic approaches. Our review describes that Class I HDACs play essential roles in all phases of neurodevelopment. Modulation of the activity of individual HDACs could be an important therapeutic approach for neurodevelopmental and psychiatric disorders.