17β-Estradiol Enhances Schwann Cell Differentiation via the ERβ-ERK1/2 Signaling Pathway and Promotes Remyelination in Injured Sciatic Nerves

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.

EphA4 Negatively Regulates Myelination by Inhibiting Schwann Cell Differentiation in the Peripheral Nervous System

“…The surgical procedure was conducted as previously described (Gu et al, 2018). Fifty adult male Sprague Dawley (SD) rats weighing 200–250 g were provided by the Experimental Animal Center of Nantong University.…”

Genome-Wide Association Study Reveals Candidate Genes for Litter Size Traits in Pelibuey Sheep

“…It was also reported in Schwann cells (SC) [81], lipid metabolic processes [82], and the reproductive process [83]. There is a relationship between E2 and SC, since it promotes SC myelination of regenerated sciatic nerves and can promote SC differentiation through the estrogen receptor beta-extracellular signal-regulated kinase 1 and 2 (ERβ-ERK1/2) signaling pathway in rats [84]. It was reported that the MTMR2 and MTMR5 genes are highly expressed in the testicles, especially in germ cells and in Sertoli, and the deactivation of any of these genes produces spermatogenic defects [83].…”

Genomic and Non-genomic Action of Neurosteroids in the Peripheral Nervous System

“…In the PNS, E2 promoted the proliferation and differentiation of SC, in vitro and in vivo, thus fostering the myelination process (Chen et al, 2016;Gu et al, 2018). By the way, some of these effects were inhibited by the antagonist of the genomic ER type α (ERα) and type β (ERβ) receptors, ICI182780 and 2-phenyl-3-(4-hydroxyphenyl)-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (PHTPP), respectively, highlighting a classical genomic mechanism.…”

“…By the way, some of these effects were inhibited by the antagonist of the genomic ER type α (ERα) and type β (ERβ) receptors, ICI182780 and 2-phenyl-3-(4-hydroxyphenyl)-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (PHTPP), respectively, highlighting a classical genomic mechanism. Nevertheless, the specific block of the intracellular signaling cascade of the extracellular signal-regulated protein kinase 1/2 (ERK1/2) or AKT (commonly downstream the activation of the membrane receptor) evidenced that also these pathways may occur, and suggested that the mechanisms are complicated, likely involving both genomic and non-genomic actions (Gu et al, 2018). Besides, also PROG was able to promote SC proliferation, and its effects appeared sex-specific (Jung-Testas et al, 1993).…”