Abstract
Oligodendrocyte precursor cells (OPCs) differentiate during postnatal development into myelin-forming oligodendrocytes, in a process distinguished by substantial changes in morphology and the onset of myelin gene expression. A mammalian-specific CNS myelin gene, tmem10, also called Opalin, encodes a type 1 transmembrane protein that is highly upregulated during early stages of OPC differentiation; however, a function for TMEM10 has not yet been identified. Here, consistent with previous studies, we detect TMEM10 protein in mouse brain beginning at ~P10 and show that protein levels continue to increase as oligodendrocytes differentiate and myelinate axons in vivo. We show that constitutive TMEM10 overexpression in the Oli-neu oligodendroglial cell line promotes the expression of the myelin-associated genes MAG, CNP and CGT, whereas TMEM10 knock down in primary OPCs reduces CNP mRNA expression and decreases the percentage of MBP-positive oligodendrocytes that differentiate in vitro. Ectopic TMEM10 expression evokes an increase in process extension and branching, and blocking endogenous TMEM10 expression results in oligodendrocytes with abnormal cell morphology. These findings may have implications for human demyelinating disorders, as oligodendrocytes expressing TMEM10 are detected in human remyelinating multiple sclerosis lesions. Together, our findings provide evidence that TMEM10 promotes oligodendrocyte terminal differentiation and may represent a novel target to promote remyelination in demyelinating disorders.
Highlights
Www.nature.com/scientificreports regulated downstream of ligands presented on the axonal surface, such as Lingo-1 and Jagged-1, and by soluble molecules secreted by neurons and neuronal activity[9,10,11,12,13]
Western blot analysis using this antibody detected one band at the expected size of ~36 KDa in lysates derived from rat Oligodendrocyte precursor cells (OPCs) cultures transfected with a control siRNA, but not in lysates of cells transfected with two different TMEM10 siRNAs (Fig. 1a)
We conclude that TMEM10 expression is upregulated in the mouse brain during oligodendrocyte differentiation and myelination in vivo
Summary
Www.nature.com/scientificreports regulated downstream of ligands presented on the axonal surface, such as Lingo-1 and Jagged-1, and by soluble molecules secreted by neurons (e.g. adenosine) and neuronal activity[9,10,11,12,13]. Multiple mechanisms have been reported that regulate oligodendrocyte differentiation, others remain to be uncovered and a comprehensive picture of developmental myelination is currently unavailable. Identifying such mechanisms is paramount, as they represent potential therapeutic targets to promote remyelination in human disorders where myelin is lost, such as Multiple Sclerosis (MS). TMEM10 was the most upregulated transcript detected during differentiation of the OPC-like Oli-neu cell line, an in vitro model of early oligodendrocyte differentiation[22]. These observations suggest that TMEM10 may influence OPC differentiation and myelination during development. Our findings provide evidence that TMEM10 promotes OPC differentiation and suggest that targeting TMEM10 signaling in oligodendrocytes may promote remyelination in demyelinating disorders
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