BMP7 retards peripheral myelination by activating p38 MAPK in Schwann cells

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 axons1. Defective myelination frequently leads to devastating diseases2. Myelin sheaths in the central nerve systems (CNS) and peripheral nerve systems (PNS) are primarily made of oligodendrocytes and Schwann cells (SCs), respectively. SCs are also required for producing extracellular matrix, modulating synaptic activity, supporting nerve development and regeneration, and providing neurotrophic support3. It is commonly accepted that transcriptional control is one main regulatory mechanism for the myelination process4. Several transcriptional components controlling myelination and differentiation of SCs have been identified, including transcriptional factors Sox10 (SRY-related HMG-box-10), Oct6 (octamer-binding transcription factor-6) and Krox20/Egr2 (early growth response-2)4. Sox10 activates Oct6, which synergistically induces the expression of Krox205. Thereafter, Krox20 takes center stage by activating numerous myelin genes such as PMP22 (peripheral myelin protein-22), MPZ (myelin protein zero) and MBP (myelin basic protein). Meanwhile, Krox20 suppresses myelination inhibitors and thus maintains SCs at myelinated state6. It has been demonstrated that cyclic AMP (cAMP) signaling pathway is essential for SC myelination in vivo and in vitro7,8. Protein kinase A (PKA) is a main downstream effector of cAMP and it plays a pivotal role for inducing myelination in SCs9. Recently, one report showed that, at the onset of myelination, G protein-coupled receptor (GPCR) Gpr126 and PKA function as a switch that allows SCs to initiate Krox20 expression and myelination10. The bone morphogenetic proteins (BMPs) belong to the transforming growth factor-β superfamily and were considered as the primary growth factors for inducing the formation of both cartilage and bone11. In the canonical pathway, BMPs activate the transcription factor SMAD (Sma and Mad related proteins) by binding to type I and type II serine/threonine kinase receptors12. The activated type I BMP receptor phosphorylates the receptor-regulated SMADs (SMAD1/5/8), which triggers the physical interaction between SMAD1/5/8 and SMAD4. Together with SMAD4, SMAD1/5/8 translocate into nucleus for inducing down-stream target gene expression. In addition, the activated receptor complex activates non-SMAD signaling pathway, such as mitogen activated protein kinase (MAPK), PP2A/p70 S6K, RhoA and TAK1/MEKK113. Besides its roles in bone formation, BMPs also play important roles for the development and differentiation of the nervous systems14. It has been reported that BMPs can inhibit neural differentiation in embryonic stem cells15; conversely, during later neuronal differentiation, BMPs in fact promote differentiation in neuronal cells16,17. Signaling by BMP4 was shown to block oligodendrocyte precursor cell maturation and regulate the timing of myelination18. Recently, it has been demonstrated that BMP4 negatively regulates myelination process in the CNS by affecting the growth and differentiation oligodendrocytes19. Sip1 has been identified as an essential modulator of CNS myelination by antagonizing BMP receptor-activated SMAD activity20. However, till to date, there is no report concerning BMPs and PNS myelination. In the present work, we showed that BMP7 significantly attenuates cAMP-induced myelin gene expression by activating p38 MAPK in SCs. Moreover, the application of BMP7 also 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.