Abstract
BackgroundMicroRNAs (miRNAs or miRs) participate in the regulation of several biological processes, including cell differentiation. Recently, miR-34a has been implicated in the differentiation of monocyte-derived dendritic cells, human erythroleukemia cells, and mouse embryonic stem cells. In addition, members of the miR-34 family have been identified as direct p53 targets. However, the function of miR-34a in the control of the differentiation program of specific neural cell types remains largely unknown. Here, we investigated the role of miR-34a in regulating mouse neural stem (NS) cell differentiation.Methodology/Principal FindingsmiR-34a overexpression increased postmitotic neurons and neurite elongation of mouse NS cells, whereas anti-miR-34a had the opposite effect. SIRT1 was identified as a target of miR-34a, which may mediate the effect of miR-34a on neurite elongation. In addition, acetylation of p53 (Lys 379) and p53-DNA binding activity were increased and cell death unchanged after miR-34a overexpression, thus reinforcing the role of p53 during neural differentiation. Interestingly, in conditions where SIRT1 was activated by pharmacologic treatment with resveratrol, miR-34a promoted astrocytic differentiation, through a SIRT1-independent mechanism.ConclusionsOur results provide new insight into the molecular mechanisms by which miR-34a modulates neural differentiation, suggesting that miR-34a is required for proper neuronal differentiation, in part, by targeting SIRT1 and modulating p53 activity.
Highlights
MicroRNAs are small,21–23 nucleotidelong regulatory RNA molecules encoded in plant and animal genomes. miRNAs regulate the expression of target genes by binding to the 39-untranslated regions of specific mRNAs and triggering mRNA destabilization or suppression of translation [1]. miRNAs appear to fine-tune gene expression by effecting more subtle and rapid changes than global transcriptional control mechanisms [2]
Our results provide new insight into the molecular mechanisms by which miR-34a modulates neural differentiation, suggesting that miR-34a is required for proper neuronal differentiation, in part, by targeting silent information regulator 1 (SIRT1) and modulating p53 activity
Results miR-34a modulates the appearance of postmitotic neurons and neurite outgrowth We have previously reported that induction of mouse neural stem (NS) cell differentiation results in a mixed cell population composed by both neuronal and glial cells, which in turn differentiate in a timecontrolled fashion within 8 days [30]
Summary
MicroRNAs (miRNAs or miRs) are small, ,21–23 nucleotidelong regulatory RNA molecules encoded in plant and animal genomes. miRNAs regulate the expression of target genes by binding to the 39-untranslated regions of specific mRNAs and triggering mRNA destabilization or suppression of translation [1]. miRNAs appear to fine-tune gene expression by effecting more subtle and rapid changes than global transcriptional control mechanisms [2]. MiRNAs regulate the expression of target genes by binding to the 39-untranslated regions of specific mRNAs and triggering mRNA destabilization or suppression of translation [1]. Functional studies indicate that miRNAs participate in the regulation of a number of cellular processes, including differentiation. The important regulatory role of miRNAs in development and differentiation clearly emerged from the study of embryonic stem cells null for the Dicer gene, which encodes an RNase III required for miRNA biogenesis. Dicer-deficient embryonic stem cells failed to differentiate. MicroRNAs (miRNAs or miRs) participate in the regulation of several biological processes, including cell differentiation. The function of miR-34a in the control of the differentiation program of specific neural cell types remains largely unknown. We investigated the role of miR-34a in regulating mouse neural stem (NS) cell differentiation
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