ABSTRACT
Earlier studies show that Hes1 expression is oscillatory in neural stem cells but sustained and high in the roof plate and the floor plate, and that such different dynamics of Hes1 expression (oscillatory versus sustained) regulate different proliferation and differentiation characteristics of these cells (active in neural stem cells but rather dormant in roof/floor plate cells). The mechanism of how different dynamics of Hes1 expression is controlled remains to be determined. Here, we found that the seed sequence of microRNA-9 (miR-9) is complementary to the 3'-UTR sequence of Hes1 mRNA. MiR-9 is highly expressed in the ventricular zone of the developing brain, which contains neural stem cells, but it is not expressed in the roof plate or the floor plate. Over-expression of miR-9 negatively regulates the Hes1 protein expression by interacting with the 3'-UTR of Hes1 mRNA, thereby inducing cell cycle exit and neuronal differentiation. Conversely, knockdown of miR-9 inhibits neuronal differentiation. Furthermore, knockdown of miR-9 inhibits the oscillatory expression of Hes1 mRNA in neural stem cells. These results indicate that miR-9 regulates the proliferation and differentiation of neural stem cells by controlling the dynamics of Hes1 expression in the developing brain.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Brain/metabolism , Cell Differentiation , Homeodomain Proteins/metabolism , MicroRNAs/metabolism , Neural Stem Cells/metabolism , 3' Untranslated Regions , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Brain/embryology , Cell Cycle , Cell Proliferation , Gene Expression Regulation, Developmental , Homeodomain Proteins/genetics , Mice , MicroRNAs/genetics , NIH 3T3 Cells , Neural Stem Cells/cytology , Neurons/cytology , Neurons/metabolism , RNA, Messenger/biosynthesis , Rats , Transcription Factor HES-1ABSTRACT
In the developing brain, neural progenitor cells switch differentiation competency by changing gene expression profiles that are governed partly by epigenetic control, such as histone modification, although the precise mechanism is unknown. Here we found that ESET (Setdb1), a histone H3 Lys9 (H3K9) methyltransferase, is highly expressed at early stages of mouse brain development but downregulated over time, and that ablation of ESET leads to decreased H3K9 trimethylation and the misregulation of genes, resulting in severe brain defects and early lethality. In the mutant brain, endogenous retrotransposons were derepressed and non-neural gene expression was activated. Furthermore, early neurogenesis was severely impaired, whereas astrocyte formation was enhanced. We conclude that there is an epigenetic role of ESET in the temporal and tissue-specific gene expression that results in proper control of brain development.
