MicroRNA‐124 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Targeting Sp1 mRNA

Mondanizadeh, Mahdieh; Arefian, Ehsan; Mosayebi, Ghasem; Saidijam, Massoud; Khansarinejad, Behzad; Hashemi, Seyed Mahmoud

doi:10.1002/jcb.25045

Cited by 53 publications

(40 citation statements)

References 37 publications

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“…Sp1 has previously been shown to be downregulated by miR‐128 in glioma cells where it has been proposed to repress Sp1 enhanced tumor formation and growth . In addition, miR‐124 has been reported to suppress Sp1 expression in mesenchymal stem cells induced to differentiate into neuron‐like cells . Our data indicate that miR‐124, ‐128, and ‐137 synergize to produce a stronger effect on Sp1 expression.…”

Section: Discussionsupporting

confidence: 54%

miR-124, -128, and -137 Orchestrate Neural Differentiation by Acting on Overlapping Gene Sets Containing a Highly Connected Transcription Factor Network

Santos

Tegge

Corrêa³

et al. 2015

Stem Cells

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The ventricular-subventricular zone harbors neural stem cells (NSCs) that can differentiate into neurons, astrocytes, and oligodendrocytes. This process requires loss of stem cell properties and gain of characteristics associated with differentiated cells. miRNAs function as important drivers of this transition; miR-124, -128, and -137 are among the most relevant ones and have been shown to share commonalities and act as proneurogenic regulators. We conducted biological and genomic analyses to dissect their target repertoire during neurogenesis and tested the hypothesis that they act cooperatively to promote differentiation. To map their target genes, we transfected NSCs with antagomiRs and analyzed differences in their mRNA profile throughout differentiation with respect to controls. This strategy led to the identification of 910 targets for miR-124, 216 for miR-128, and 652 for miR-137. The target sets show extensive overlap. Inspection by gene ontology and network analysis indicated that transcription factors are a major component of these miRNAs target sets. Moreover, several of these transcription factors form a highly interconnected network. Sp1 was determined to be the main node of this network and was further investigated. Our data suggest that miR-124, -128, and -137 act synergistically to regulate Sp1 expression. Sp1 levels are dramatically reduced as cells differentiate and silencing of its expression reduced neuronal production and affected NSC viability and proliferation. In summary, our results show that miRNAs can act cooperatively and synergistically to regulate complex biological processes like neurogenesis and that transcription factors are heavily targeted to branch out their regulatory effect. STEM CELLS 2016;34:220-232 SIGNIFICANCE STATEMENTWe demonstrate here, perhaps for the first time, that miRNAs (miR-124, -128 and -137) can act cooperatively to regulate a complex biological problem such as neurogenesis. They do so by targeting overlapping sets of genes. Moreover, our genomic analyses determined that transcription factors are the main component of their target sets. Our results indicate additional associations between the three analyzed miRNA and the targeted TFs. Based on described ChIP analysis, we suggest that miR-124, -128 and -137 and their targeted TFs could act on overlapping and related target sets producing different functional outcomes that ultimately would influence the balance self-renewal/differentiation.

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Section: Discussionsupporting

confidence: 54%

miR-124, -128, and -137 Orchestrate Neural Differentiation by Acting on Overlapping Gene Sets Containing a Highly Connected Transcription Factor Network

Santos

Tegge

Corrêa³

et al. 2015

Stem Cells

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“…Our data further suggest that the downregulation of Sox9 and Ptbp1 by miR‐124 is necessary for neuronal differentiation. Accordingly, Mondanizadeh et al reported an increase of miR‐124 expression during neurogenesis in adipose‐derived mesenchymal stem cells by targeting Sp1 mRNA (Mondanizadeh et al, ). miR‐124 targets cellular gene expression including repression of transcription factor Sox9 in SVZ stem cells (Cheng, Pastrana, Tavazoie, & Doetsch, ) and it reduces RNA‐binding protein PTBP1 (Makeyev, Zhang, Carrasco, & Maniatis, ).…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, Mondanizadeh et al reported an increase of miR-124 expression during neurogenesis in adipose-derived mesenchymal stem cells by targeting Sp1 mRNA (Mondanizadeh et al, 2015).…”

Section: Stem Cells Express Master Regulatorsmentioning

confidence: 99%

miR‐124 promotes neural differentiation in mouse bulge stem cells by repressing Ptbp1 and Sox9

Mokabber

Najafzadeh

Mohammadzadeh-Vardin

2018

Journal Cellular Physiology

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Hair follicle stem cells (HFSCs) are able to differentiate into neurons and glial cells. Distinct microRNAs (miRNAs) regulate the proliferation and differentiation of HFSCs. However, the exact role of miR‐124 in the neural differentiation of HFSCs has not been elucidated. HFSCs were isolated from mouse whisker follicles. miR‐9, let‐7b, and miR‐124, Ptbp1 , and Sox9 expression levels were detected by real‐time polymerase chain reaction (RT‐PCR). The influence of miR‐124 transfection was evaluated using immunostaining. We demonstrated that miR‐124 and let‐7b expression levels were significantly increased after the neural differentiation. Sox9 and Ptbp1 were identified as the target of miR‐124 in the HFSCs. During neural differentiation and miR‐124 mimicking, Ptbp1 and Sox9 levels were decreased. Moreover, the miR‐124 overexpression increased MAP2 (58.43 ± 11.26) and NeuN (48.34 ± 11.15) proteins expression. The results demonstrated that miR‐124 may promote the differentiation of HFSCs into neuronal cells by targeting Sox9 and Ptbp1.

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“…Most recently, it was demonstrated that miR-124 is able to suppress Sp1 expression, which in turn affected the neuronal differentiation of mesenchymal stem cells [28]. miR-124 could directly target SCP1, which play a key role in the neuronal differentiation of ADSC [29].…”

Section: Discussionmentioning

confidence: 99%

miR-142-5p Improves Neural Differentiation and Proliferation of Adipose-Derived Stem Cells

Yang¹,

Wang²,

Wu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: MiRNAs may regulate neurogenic differentiation of adipose-derived stem cells (ADSCs). In this study, we hypothesized that the miR-142-5p can repress the expression of RhoA/ROCK1 pathway on the neurogenesis of ADSCs. Methods: Deregulated miRNA during neurogenic differentiation of ADSCs were identified. The expression of neuron-specific enolase (NSE) and β III tubulin (Neuron-specific class III beta-tubulin) were detected as the markers of neurogenic differentiation by immunostaining and western blot. The targeting of miR-142-5p on RhoA and ROCK1 was verified by dual luciferase assay, qRT-PCR and western blot. The roles of miR-142-5p and the RhoA/ROCK1 signaling pathway were explored by using functional experiments including cell viability and colony formation assays. Results: MiR-142-5p is significantly upregulated during neurogenic differentiation of ADSCs. Knockdown of endogenous miR-142-5p hampered neurogenic differentiation. MiR-142-5p could directly target RhoA and ROCK1 mRNA and repress their expressions, through which it increased the proportion of differentiated cells with positive NSE and β III tubulin. RhoA/ROCK1 signaling pathway is involved in miR-142-5p effect on the process of neurogenic differentiation of ADSCs. Conclusion: Our results demonstrate that miR-142-5p functions as a growth promotive miRNA and plays an important role in neurogenic differentiation by targeting RhoA/ROCK1 in ADSCs.

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MicroRNA‐124 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Targeting Sp1 mRNA

Cited by 53 publications

References 37 publications

miR-124, -128, and -137 Orchestrate Neural Differentiation by Acting on Overlapping Gene Sets Containing a Highly Connected Transcription Factor Network

miR-124, -128, and -137 Orchestrate Neural Differentiation by Acting on Overlapping Gene Sets Containing a Highly Connected Transcription Factor Network

miR‐124 promotes neural differentiation in mouse bulge stem cells by repressing Ptbp1 and Sox9

miR-142-5p Improves Neural Differentiation and Proliferation of Adipose-Derived Stem Cells

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