miR-23regulation of lamin B1 is crucial for oligodendrocyte development and myelination

Abstract

SUMMARYDuplication 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.

Integrative nucleophosmin mutation-associated microRNA and gene expression pattern analysis identifies novel microRNA - target gene interactions in acute myeloid leukemia

“…For data normalization three different housekeeping genes (ACTB, LMNB1, PGK1) were utilized as endogenous controls (Figure 3), because housekeeping genes themselves can be targeted by miRNAs (Online Supplementary Table S6). For example, normalization of the measurements for SPARC and IRF2 using LMNB1, known to be targeted by miR-23a, 20 might lead to misinterpretation of results if compared to normalization with the other housekeeping genes ( Figure 3, open symbols; Online Supplementary Table S8).…”

MicroRNA-23a promotes myelination in the central nervous system

“…We have previously shown that miR-23 overexpression enhances OL maturation in an established culture system (11). In addition, miR-23a and miR-23b are both up-regulated in OL under differentiation conditions compared with progenitor status under proliferation conditions (Fig.…”

“…The repression of PTEN and enhancement of 2700046G09Rik by miR23a were validated by mutagenizing their respective miR-23a binding elements (Fig. S5 B-D) miR-23 exhibits a gradually increased expression pattern during postnatal development (11), and the true direct target genes of miR-23a should display expression patterns correlating with miR-23a expression. Indeed, the protein levels of PTEN display a gradual decrease from postnatal day 1 to 10 months of age (Fig.…”

“…miR-23 is among the most abundant miRNAs in OLs (6,7). Previously, we reported that in the presence of excess miR-23 in vitro, a greater proportion of cells express mature markers of OLs that are paralleled by multipolar morphological appearance with increased levels of mature myelin proteins, indicating that miR-23 can enhance oligodendrogenesis (11). In contrast, excessive lamin B1, a nuclear envelope protein and target of miR-23, leads to lower numbers of cells expressing mature markers with reduced levels of mature myelin proteins both in vitro and in vivo, suggesting defective differentiation of OLs.…”

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

“…(2013) provided new mechanisms of lamin B1 regulation, implicating miR‐23a (Lin & Fu, 2009; Lin et al., 2013). They first demonstrated that lamin B1 expression was developmentally regulated as the protein decreased in the mouse brain from birth to 300 days of age, while miR‐23a levels progressively increased in parallel.…”