miR-23 regulation of lamin B1 is crucial for oligodendrocyte development and myelination.
Duplication of the gene encoding lamin B1 (LMNB1) with increased mRNA and protein levels has been shown to cause severe myelin loss in the brains of adult-onset autosomal dominant leukodystrophy patients. Similar to many neurodegenerative disorders, patients with adult-onset autosomal dominant leukodystrophy are phenotypically normal until adulthood and the defect is specific to the central nervous system despite the ubiquitous expression pattern of lamin B1. We set out to dissect the molecular mechanisms underlying this demyelinating phenotype. Increased lamin B1 expression results in disturbances of inner nuclear membrane proteins, chromatin organization and nuclear pore transport in vitro. It also leads to premature arrest of oligodendrocyte differentiation, which might be caused by reduced transcription of myelin genes and by mislocalization of myelin proteins. We identified the microRNA miR-23 as a negative regulator of lamin B1 that can ameliorate the consequences of excessive lamin B1 at the cellular level. Our results indicate that regulation of lamin B1 is important for myelin maintenance and that miR-23 contributes to this process, at least in part, by downregulating lamin B1, therefore establishing novel functions of lamin B1 and miR-23 in the regulation of oligodendroglia development and myelin formation in vitro.
Lin
Shu-Ting
ST
Department of Neurology, University of California San Francisco, 94158, USA.
Fu
Ying-Hui
YH
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D020440:Gene Duplication; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D034921:Lamin Type B / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D009186:Myelin Sheath / Q000378:metabolism / Q000502:physiology*; D009836:Oligodendroglia / Q000502:physiology*; D010641:Phenotype
D002843:Chromatin; D034921:Lamin Type B; D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse