title: MiR-125a-3p timely inhibits oligodendroglial maturation and is pathologically up-regulated in human multiple sclerosis.
abstract: In the mature central nervous system (CNS), oligodendrocytes provide support and insulation to axons thanks to the production of a myelin sheath. During their maturation to myelinating cells, oligodendroglial precursors (OPCs) follow a very precise differentiation program, which is finely orchestrated by transcription factors, epigenetic factors and microRNAs (miRNAs), a class of small non-coding RNAs involved in post-transcriptional regulation. Any alterations in this program can potentially contribute to dysregulated myelination, impaired remyelination and neurodegenerative conditions, as it happens in multiple sclerosis (MS). Here, we identify miR-125a-3p, a developmentally regulated miRNA, as a new actor of oligodendroglial maturation, that, in the mammalian CNS regulates the expression of myelin genes by simultaneously acting on several of its already validated targets. In cultured OPCs, over-expression of miR-125a-3p by mimic treatment impairs while its inhibition with an antago-miR stimulates oligodendroglial maturation. Moreover, we show that miR-125a-3p levels are abnormally high in the cerebrospinal fluid of MS patients bearing active demyelinating lesions, suggesting that its pathological upregulation may contribute to MS development, at least in part by blockade of OPC differentiation leading to impaired repair of demyelinated lesions.
authors.affiliation: Laboratory of Molecular and Cellular Pharmacology of the Purinergic Transmission, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, 20133, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Lecca
authors.affiliation: Laboratory of Molecular and Cellular Pharmacology of the Purinergic Transmission, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, 20133, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Marangon
authors.affiliation: Laboratory of Molecular and Cellular Pharmacology of the Purinergic Transmission, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, 20133, Italy.
authors.forename: Giusy T
authors.initials: GT
authors.lastname: Coppolino
authors.affiliation: Departamento de Bioquímica y Biología Molecular IV, Universidad Complutense de Madrid, 28040, Spain.
authors.forename: Aida Menéndez
authors.initials: AM
authors.lastname: Méndez
authors.affiliation: Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan, 20132, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Finardi
authors.affiliation: Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan, 20132, Italy.
authors.forename: Gloria Dalla
authors.initials: GD
authors.lastname: Costa
authors.affiliation: Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan, 20132, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Martinelli
authors.affiliation: Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan, 20132, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Furlan
authors.affiliation: Laboratory of Molecular and Cellular Pharmacology of the Purinergic Transmission, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, 20133, Italy.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Abbracchio
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: C531888:MIRN125 microRNA, human; D035683:MicroRNAs