Astrocytes induce proliferation of oligodendrocyte progenitor cells via connexin 47-mediated activation of the ERK/Id4 pathway

Abstract

The proliferative ability of oligodendrocyte progenitor cells (OPCs) varied markedly under different culture conditions. Astrocytes (ASTs) have been verified to play a major role in regulating the proliferation of OPCs through direct contact. However, the mechanisms have not been fully clarified. To investigate the effect and mechanism under AST and OPC co-culture conditions, we analyzed all connexins comprehensively in OPCs under OPC mono-culture, AST-secreted cell factor co-culture and AST-OPC direct-contact co-culture, and found that significantly differentially expressed Cx47 was the most significant. To assess whether Cx47 plays a role in proliferation, Cx47 siRNA were conducted. The result indicates that the cell cycle of OPCs was changed, and the cell proliferation was markedly inhibited. Kyoto Encyclopedia of Genes and Genomes (KEGG) predictive analysis suggested that Cx47 regulate cell cycle and proliferation by Ca 2C activation of ERK1/2. To verify the prediction, flow cytometry, confocal microscopy, 5-ethynyl-2 0 -deoxyuridine (EdU), polymerase chain reaction (RT-PCR) and western blot were used. The results show that interference of Cx47 led to decreased Ca 2C concentrations, lower p-ERK 1/2 levels, reduced transcription factor inhibitor of DNA binding 4 (Id4) expression, arrested cell cycle and reduced OPCs proliferative ability. Additionally, blocking ERK1/2 signaling caused decreased Id4 expression, arrested cell cycle in G1 phase, and reduced OPCs proliferative ability. In conclusion, ASTs can cause Ca 2C signaling activation, ERK1/2 phosphorylation, and Id4 expression stimulation in OPCs, inducing proliferation of these cells, mainly through Cx47.

Connexin and Pannexin-Based Channels in Oligodendrocytes: Implications in Brain Health and Disease

“…The evidence discussed in this review indicates that both oligodendrocyte-oligodendrocyte coupling (mainly mediated by Cx47 and Cx32 homotypic GJCs) and oligodendrocyte-astrocyte coupling (mediated by Cx47/Cx43 or Cx32/Cx30 pairs) play a pivotal role in forming a functional panglial syncytium supporting the buffering of extracellular K + and metabolic supply to axons. Although the available literature suggests that oligodendrocyte progenitors would not contribute to this functional syncytial network, their role could not be completely ruled out based on recent findings showing the coupling of OPCs with astrocytes through Cx47 (Liu et al, 2017; Xu et al, 2017). Future research will elucidate whether OPCs make part of this interconnected glial network.…”

Prenatal valproic acid on the basis of gestational diabetes also induces autistic behavior and disrupts myelination and oligodendroglial maturation slightly in offspring

“…6C-d). The MAPK signaling pathway in neurons, astrocytes, and microglia, when inhibited by the in vivo injection of U0126, impacted OPCs variably [73] . Moreover, OPC differentiation induced by the ERK inhibitor could not restore processes in chronic demyelination [74] .…”

Connexins in the Central Nervous System: Physiological Traits and Neuroprotective Targets

“…This has led to a growing in-depth research focusing on cellular and molecular mechanisms underlying neurodegeneration to increasingly counteract this phenomenon. In human and in experimental models, a number of Cx alterations are differently involved in the development of various neurodegenerative diseases so much so that they are considered important therapeutic targets (Belousov et al, 2017 ; Charvériat et al, 2017 ; Liu et al, 2017 ). Several independent studies have pointed out that onset and progression of homeostatic imbalances observed during neurodegeneration could be associated with a GJ-independent increased membrane permeability related to HCs activity in the CNS (Retamal et al, 2007 ; Orellana et al, 2010 ; Burkovetskaya et al, 2014 ).…”