MicroRNAs are a class of small non-coding RNA molecules that control gene expression by binding to complementary sequences in the 3’ untranslated regions of their target messenger RNAs, therefore resulting in either translational repression or degradation. In the last years, it has been demonstrated that several miRNA families are brain-enriched and that they exert important roles in the nervous system development. We focused our attention on a miRNA already known to be involved in neural processes, such as neural commitment and astroglial differentiation, however, its role in oligodendrocytes has never been investigated. First, to evaluate the potential relevance of this miRNA in oligodendrocyte differentiation and myelination, we used a gene ontology-based approach, demonstrating that its targets are significantly enriched in biological processes related to oligodendrocyte development. Thus, we characterized the expression pattern of this miRNA in physiology, showing that it is expressed in oligodendroglial cells throughout brain development and that it is progressively up-regulated during OPC in vitro differentiation. Interestingly, we also found that the over-expression of this miRNA impairs, whereas its silencing promotes oligodendrocyte maturation. To evaluate the pathways potentially involved in these mechanisms, we took advantage of Ingenuity Pathway Analysis tool (IPA), building a model network containing known players of oligodendrogliogenesis and already validated targets of this miRNA. This analysis revealed that intracellular kinases such as Fyn and p38, cytoskeletal proteins and neuregulins can directly or indirectly promote the differentiation, suggesting that this miRNA, through the simultaneous inhibition of these targets, leads to delay in oligodendroglial maturation. Moreover, we found that its levels are altered in both brain active lesions and cerebrospinal fluid of multiple sclerosis patients, suggesting that it could be a useful biomarker of disease. The identification of a new miRNA modulating oligodendrocyte differentiation provide new findings about the complex regulation of myelination processes and it is conceivable that an antago-miRNA specific for this miRNA may help in promoting oligodendrocyte maturation in diseases characterized by impaired myelin repair.
A new miRNA regulating oligodendrocyte maturation in physiology and disease / D. Marangon, G.T. Coppolino, A. Finardi, R. Furlan, M.P. Abbracchio, D. Lecca. ((Intervento presentato al convegno Next Step 7 : la giovane ricerca avanza tenutosi a Milano nel 2016.
A new miRNA regulating oligodendrocyte maturation in physiology and disease
D. Marangon;G.T. Coppolino;M.P. Abbracchio;D. Lecca
2016
Abstract
MicroRNAs are a class of small non-coding RNA molecules that control gene expression by binding to complementary sequences in the 3’ untranslated regions of their target messenger RNAs, therefore resulting in either translational repression or degradation. In the last years, it has been demonstrated that several miRNA families are brain-enriched and that they exert important roles in the nervous system development. We focused our attention on a miRNA already known to be involved in neural processes, such as neural commitment and astroglial differentiation, however, its role in oligodendrocytes has never been investigated. First, to evaluate the potential relevance of this miRNA in oligodendrocyte differentiation and myelination, we used a gene ontology-based approach, demonstrating that its targets are significantly enriched in biological processes related to oligodendrocyte development. Thus, we characterized the expression pattern of this miRNA in physiology, showing that it is expressed in oligodendroglial cells throughout brain development and that it is progressively up-regulated during OPC in vitro differentiation. Interestingly, we also found that the over-expression of this miRNA impairs, whereas its silencing promotes oligodendrocyte maturation. To evaluate the pathways potentially involved in these mechanisms, we took advantage of Ingenuity Pathway Analysis tool (IPA), building a model network containing known players of oligodendrogliogenesis and already validated targets of this miRNA. This analysis revealed that intracellular kinases such as Fyn and p38, cytoskeletal proteins and neuregulins can directly or indirectly promote the differentiation, suggesting that this miRNA, through the simultaneous inhibition of these targets, leads to delay in oligodendroglial maturation. Moreover, we found that its levels are altered in both brain active lesions and cerebrospinal fluid of multiple sclerosis patients, suggesting that it could be a useful biomarker of disease. The identification of a new miRNA modulating oligodendrocyte differentiation provide new findings about the complex regulation of myelination processes and it is conceivable that an antago-miRNA specific for this miRNA may help in promoting oligodendrocyte maturation in diseases characterized by impaired myelin repair.File | Dimensione | Formato | |
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