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Abstract
Schwann cell (SC) myelination is pivotal for the proper physiological functioning of the nervous system, but the underlying molecular mechanism remains less well understood. Here, we showed that the expression of bone morphogenetic protein 7 (BMP7) inversely correlates with myelin gene expression during peripheral myelination, which suggests that BMP7 is likely a negative regulator for myelin gene expression. Our experiments further showed that the application of BMP7 attenuates the cAMP induced myelin gene expression in SCs. Downstream pathway analysis suggested that both p38 MAPK and SMAD are activated by exogenous BMP7 in SCs. The pharmacological intervention and gene silence studies revealed that p38 MAPK, not SMAD, is responsible for BMP7-mediated suppression of myelin gene expression. In addition, c-Jun, a potential negative regulator for peripheral myelination, was up-regulated by BMP7. In vivo experiments showed that BMP7 treatment greatly impaired peripheral myelination in newborn rats. Together, our results established that BMP7 is a negative regulator for peripheral myelin gene expression and that p38 MAPK/c-Jun axis might be the main downstream target of BMP7 in this process.
Highlights
Myelination of axons is an essential process for the proper physiological functioning of the nervous system, as myelin sheaths allow fast propagation of nerve impulses by saltatory conduction in axons[1]
The application of bone morphogenetic protein 7 (BMP7) impairs peripheral myelination in newborn rats. These results showed that BMP7 is a negative regulator for peripheral myelination and is potentially a drug target for the treatment of disorders associated with dysregulated peripheral myelination, such as the Charcot-Marie-Tooth disease
bone morphogenetic proteins (BMPs) are involved in the peripheral nerve systems (PNS) myelination process, we first measured the mRNA levels of BMPs and Krox[20] in sciatic nerves during development
Summary
Myelination of axons is an essential process for the proper physiological functioning of the nervous system, as myelin sheaths allow fast propagation of nerve impulses by saltatory conduction in axons[1]. Protein kinase A (PKA) is a main downstream effector of cAMP and it plays a pivotal role for inducing myelination in SCs9. One report showed that, at the onset of myelination, G protein-coupled receptor (GPCR) Gpr[126] and PKA function as a switch that allows SCs to initiate Krox[20] expression and myelination[10]. BMPs activate the transcription factor SMAD (Sma and Mad related proteins) by binding to type I and type II serine/threonine kinase receptors[12]. It has been demonstrated that BMP4 negatively regulates myelination process in the CNS by affecting the growth and differentiation oligodendrocytes[19]. We showed that BMP7 significantly attenuates cAMP-induced myelin gene expression by activating p38 MAPK in SCs. the application of BMP7 impairs peripheral myelination in newborn rats. These results showed that BMP7 is a negative regulator for peripheral myelination and is potentially a drug target for the treatment of disorders associated with dysregulated peripheral myelination, such as the Charcot-Marie-Tooth disease
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