Abstract
Remyelination is critical for nerve regeneration. However, the molecular mechanism involved in remyelination is poorly understood. To explore the roles of 17β-estradiol (E2) for myelination in the peripheral nervous system, we used a co-culture model of rat dorsal root ganglion (DRG) explants and Schwann cells (SCs) and a regeneration model of the crushed sciatic nerves in ovariectomized (OVX) and non-ovariectomized (non-OVX) rats for in vitro and in vivo analysis. E2 promoted myelination by facilitating the differentiation of SCs in vitro, which could be inhibited by the estrogen receptors (ER) antagonist ICI182780, ERβ antagonist PHTPP, or ERK1/2 antagonist PD98059. This suggests that E2 accelerates SC differentiation via the ERβ-ERK1/2 signaling. Furthermore, E2 promotes remyelination in crushed sciatic nerves of both OVX and non-OVX rats. Interestingly, E2 also significantly increased the expression of the lysosome membrane proteins LAMP1 and myelin protein P0 in the regenerating nerves. Moreover, P0 has higher degree of colocalization with LAMP1 in the regenerating nerves. Taking together, our results suggest that E2 enhances Schwann cell differentiation and further myelination via the ERβ-ERK1/2 signaling and that E2 increases the expression of myelin proteins and lysosomes in SCs to promotes remyelination in regenerating sciatic nerves.
Highlights
Axon myelination is essential for rapid salutatory impulse conduction in the vertebrate nervous system during both development and nerve regeneration following injury (Taveggia et al, 2010; Pereira et al, 2012)
After 4 weeks of dorsal root ganglion (DRG)/Schwann cells (SCs) co-culture, a typical myelin-like segregation structures can be observed under phase-contrast microscope (Figure 1A), which was confirmed by the expression of the myelin protein myelin associated glycoprotein (MAG) with immunohistochemistry (Figure 1B)
These results indicated that E2 enhances myelination in vitro
Summary
Axon myelination is essential for rapid salutatory impulse conduction in the vertebrate nervous system during both development and nerve regeneration following injury (Taveggia et al, 2010; Pereira et al, 2012). The multi-layered myelin sheaths around axons are generated by plasma membranes of specialized glial cells: oligodendrocytes (OLs) in the central nervous system (CNS) and Schwann cells (SCs) in the peripheral nervous system (PNS). Studies have suggested that E2 may regulate myelination and remyelination in both the central and peripheral nervous systems (Melcangi et al, 2003; Schumacher et al, 2007; Zhu and Glaser, 2008; Chen et al, 2016). Whether estrogen promotes peripheral nerve myelination and remyelination via the AKT or ERK signaling pathway remains unknown
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