PRICKLE1 AS POSITIVE REGULATOR OF OLIGODENDROCYTE DIFFERENTIATION

Spontaneous neural repair from endogenous neural stem cells' (NSCs) niches occurs in response to central nervous system (CNS) injuries to only a limited extent. Uncovering the mechanisms that control neural repair and can be further manipulated to promote NSCs toward oligodendrocyte progenitors cells (OPCs) and myelinating oligodendrocytes is a major objective. In the current study, we describe high-throughput transcriptional changes in adult mouse subventricular zone (SVZ)-NSCs during differentiation in vitro. In order to identify myelin-specific transcriptional regulators among large transcriptional changes associated with differentiation, we have focused on transcripts encoding transcription factors and regulators showing expression profile that is highly correlated with expression of myelin-encoding genes. We have revealed previously undescribed effect of Prickle1 and Nfe2l3 transcriptional regulators that are positively correlated with expression of myelin basic protein (MBP). Using Prickle1 and Nfe2l3 silencing and immunocytochemistry approaches, we demonstrated that silencing of Prickle1 dramatically decreases differentiation to NG2(+) OPCs while Nfe2l3 moderately decreases as compared with control siRNA. Moreover, silencing of Prickle1 also decreases maturation of OPCs to MBP(+)oligodendrocytes (OLs). Accordingly, overexpression of Prickle1 increases the differentiation of NSCs to CNPase(+) pre-myelinating and myelinating MBP+ OLs. In particular, the necessity of Prickle1 for oligodendrocyte differentiation is demonstrated in purified OPCs cultures. Our findings demonstrate the role of Prickle1 in positive regulation of differentiation and maturation of oligodendrocytes suggesting that targeting Prickle1 in CNS injuries and particularly in demyelinating disease could promote generation of myelinating oligodendrocytes from endogenous niches to replenish damaged oligodendrocytes. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.