miR-34a Regulates Mouse Neural Stem Cell Differentiation

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.

MicroRNA‐432 contributes to dopamine cocktail and retinoic acid induced differentiation of human neuroblastoma cells by targeting NESTIN and RCOR1 genes

“…Expression of miR-145 was decreased significantly at day 3 but expression was increased at day 7. Expressions of let-7a, miR-100, miR-124, miR-125b, miR-137 and miR-34a have been reported to increase in other publications [29,30]. Expression of miR-16 has also been reported to increase [31].…”

Upregulated sirtuin 1 by miRNA-34a is required for smooth muscle cell differentiation from pluripotent stem cells

“…16,25,26 It has been recently reported that suppression of somatic cell reprogramming into pluripotent cells by miR-34a was due to their repression of pluripotency genes, 27 implying that miR-34a could have an important role in stem cell differentiation. Indeed, recent studies show that miR-34a has a role in neural 28 and megakaryocytic differentiation 29 and is a critical cell-fate determinant in early-stage dividing colon cancer stem cells. 30 In the present study, we provide compelling evidence to support a critical role of miR-34a in SMC differentiation.…”

MicroRNAs in neuroblastoma differentiation and differentiation therapy

“…However, there are limited in vivo studies specifically focusing on miRNA-based differentiation therapies in neuroblastoma. For example, miR-34a has been found to have a strong differentiation-inducing function [21,[47][48][49][50] ; however, the effect of miR-34 mimic treatment on neuroblastoma differentiation was not investigated in the above study on miR-34a mimic [77] . The study in our group has shown the therapeutic promise of the differentiation-inducing miRNA mimics of miR-506-3p and miR-449a using in vitro approaches [21,51] ; in vivo therapeutic investigations on these miRNAs certainly need be pursued in the future.…”

“…that inducing cell differentiation may play a key role in the tumor suppressive function of miR-34a [50] . The study performed by Aranha et al observed cell differentiation in mouse neural stem cells following the overexpression of miR-34a [50] .…”

“…The study performed by Aranha et al observed cell differentiation in mouse neural stem cells following the overexpression of miR-34a [50] . The study done by Agostini et al also showed the importance of this miRNA in neuronal development [48] .…”