miR-34a regulates cell proliferation, morphology and function of newborn neurons resulting in improved behavioural outcomes

Mollinari, Cristiana; Racaniello, Mauro; Berry, Alessandra; Pieri, Massimo; Stefano, Maria Chiara de; Cardinale, Alessio; Zona, Cristina; Cirulli, Francesca; Garaci, Enrico; Merlo, Daniela

doi:10.1038/cddis.2014.589

Cited by 45 publications

(38 citation statements)

References 60 publications

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“…Furthermore, several other miRs have also been revealed to mediate the proliferation of neural cells. The overexpression of miR-125b, for example, inhibited the proliferation of neural stem/progenitor cells (22), and miR-34a was revealed to enhance cell proliferation and function of newly generated neurons, as well as improve behavioral outcomes (23). Furthermore, as patients with AD are characterized by learning and memory deficits (24), SAMP8 mice were used to investigate the effect of miR-135b on learning and memory behaviors in the present study.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-135b has a neuroprotective role via targeting of β-site APP-cleaving enzyme 1

Zhang

Xing

Guo

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. MicroRNAs (miRs) are a class of endogenous small non-coding RNAs that have been revealed to negatively mediate the expression of their target genes at the post-transcriptional level. Recently, particular miRs have demonstrated an involvement in the pathogenesis of Alzheimer's disease (AD). However, the specific role of miR-135b in AD has yet to be elucidated. The present study aimed to investigate the neuroprotective role of miR-135b, in addition to its underlying mechanism. Herein, reverse transcription-quantitative polymerase chain reaction was conducted to determine miR-135b expression levels in the peripheral blood samples of patients with AD and age-matched normal controls. The data of the present study revealed that the expression levels of miR-135b were significantly reduced in the peripheral blood of AD patients compared with normal controls (P<0.01). In vitro MTT analyses identified that the overexpression of miR-135b significantly enhanced the proliferation of hippocampal cells (P<0.01). Furthermore, in vivo analysis using a Y-maze test indicated that injection with miR-135b mimics into the third ventricle of anesthetized SAMP8 mice significantly enhanced their learning and memory capacities (P<0.01). Molecular mechanism investigations identified β-site APP-cleaving enzyme 1 (BACE1) as a direct target gene of miR-135b, and the latter was identified to negatively mediate the protein expression levels of BACE1 in hippocampal cells, in addition to hippocampal tissues, of SAMP8 mice. Based on the aforementioned findings, we propose that miR-135b has a neuroprotective role via direct targeting of BACE1 and, thus, may be used for the treatment of AD.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-135b has a neuroprotective role via targeting of β-site APP-cleaving enzyme 1

Zhang

Xing

Guo

et al. 2016

Experimental and Therapeutic Medicine

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“…Chang and coworkers43 reported that the decreased expression of miR‐34a is crucial for the precise deployment of neural precursors to their correct destination. Similarly, Mollinari and coauthors44 identified DCX , a gene involved in neuronal migration disorders, as a new target of miR‐34a; they also observed stage‐specific effects of the overexpression of miR‐34a, detecting an increase in cell proliferation, and a delay in neuroblast migration. Thus, it could be hypothesized that the laminar disorganization and loss of radial orientation45 typically found in FCD type II may also be related to the dysregulation in the expression of hsa‐miR‐34a.…”

Section: Discussionmentioning

confidence: 85%

Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia

Avansini

Torres

Vieira

et al. 2018

Annals of Neurology

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ObjectiveFocal cortical dysplasias (FCDs) are an important cause of drug‐resistant epilepsy. In this work, we aimed to investigate whether abnormal gene regulation, mediated by microRNA, could be involved in FCD type II.MethodsWe used total RNA from the brain tissue of 16 patients with FCD type II and 28 controls. MicroRNA expression was initially assessed by microarray. Quantitative polymerase chain reaction, in situ hybridization, luciferase reporter assays, and deep sequencing for genes in the mTOR pathway were performed to validate and further explore our initial study.Resultshsa‐let‐7f (p = 0.039), hsa‐miR‐31 (p = 0.0078), and hsa‐miR34a (p = 0.021) were downregulated in FCD type II, whereas a transcription factor involved in neuronal and glial fate specification, NEUROG2 (p < 0.05), was upregulated. We also found that the RND2 gene, a NEUROG2‐target, is upregulated (p < 0.001). In vitro experiments showed that hsa‐miR‐34a downregulates NEUROG2 by binding to its 5′‐untranslated region. Moreover, we observed strong nuclear expression of NEUROG2 in balloon cells and dysmorphic neurons and found that 28.5% of our patients presented brain somatic mutations in genes of the mTOR pathway.InterpretationOur findings suggest a new molecular mechanism, in which NEUROG2 has a pivotal and central role in the pathogenesis of FCD type II. In this way, we found that the downregulation of hsa‐miR‐34a leads to upregulation of NEUROG2, and consequently to overexpression of the RND2 gene. These findings indicate that a faulty coupling in neuronal differentiation and migration mechanisms may explain the presence of aberrant cells and complete dyslamination in FCD type II. Ann Neurol 2018;83:623–635

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“…In human beings, there are ~1,600 miRNAs, which regulate more than half of protein coding genes, and each miRNA can regulate multiple proteins 174. Because the brain expresses several unique miRNAs such as miR-34a that control dendritic morphology, ion channel level, neuronal migration, and glial function microRNA may have an important implication for neuropsychiatric disorders 175. For example, miR-34a affected bipolar risk through directly impacting the ANK3 and CACNB3 expressions,176 and upregulation of miR-34a is associated with the risk of epilepsy 177.…”

Section: Epigenetics Of Epilepsymentioning

confidence: 99%

“…miRNAs regulates neural differentiation, maintenance, and plasticity. Fragile X mental retardation protein (FMRP) results in epilepsy associated with Fragile X syndrome by glutaminergic and GABAergic synaptic dysfunctions at the mRNA and protein levels 175–177…”

Section: Epigenetics Of Epilepsymentioning

confidence: 99%

Genetic and epigenetic mechanisms of epilepsy: a review

Chen

Giri²,

Xia

et al. 2017

NDT

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Epilepsy is a common episodic neurological disorder or condition characterized by recurrent epileptic seizures, and genetics seems to play a key role in its etiology. Early linkage studies have localized multiple loci that may harbor susceptibility genes to epilepsy, and mutational analyses have detected a number of mutations involved in both ion channel and nonion channel genes in patients with idiopathic epilepsy. Genome-wide studies of epilepsy have found copy number variants at 2q24.2-q24.3, 7q11.22, 15q11.2-q13.3, and 16p13.11-p13.2, some of which disrupt multiple genes, such as NRXN1, AUTS2, NLGN1, CNTNAP2, GRIN2A, PRRT2, NIPA2, and BMP5, implicated for neurodevelopmental disorders, including intellectual disability and autism. Unfortunately, only a few common genetic variants have been associated with epilepsy. Recent exome-sequencing studies have found some genetic mutations, most of which are located in nonion channel genes such as the LGI1, PRRT2, EFHC1, PRICKLE, RBFOX1, and DEPDC5 and in probands with rare forms of familial epilepsy, and some of these genes are involved with the neurodevelopment. Since epigenetics plays a role in neuronal function from embryogenesis and early brain development to tissue-specific gene expression, epigenetic regulation may contribute to the genetic mechanism of neurodevelopment through which a gene and the environment interacting with each other affect the development of epilepsy. This review focused on the analytic tools used to identify epilepsy and then provided a summary of recent linkage and association findings, indicating the existence of novel genes on several chromosomes for further understanding of the biology of epilepsy.

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miR-34a regulates cell proliferation, morphology and function of newborn neurons resulting in improved behavioural outcomes

Cited by 45 publications

References 60 publications

MicroRNA-135b has a neuroprotective role via targeting of β-site APP-cleaving enzyme 1

MicroRNA-135b has a neuroprotective role via targeting of β-site APP-cleaving enzyme 1

Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia

Genetic and epigenetic mechanisms of epilepsy: a review

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