Molecular regulation of myelination by Oligodendrocyte Progenitor cells
Vora, Parvez Firoz
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Oligodendrocytes (OL) are the myelinating cells of the central nervous system (CNS). A series of complex cell signaling events in the CNS ensures successful myelination. Various molecular cues including growth factors, transcription factors and cytokines regulate myelination by inducing OL migration, proliferation and differentiation. Plateletderived growth factor A (PDGF-A) and fibroblast growth factor 2 (FGF2) are two of the most well characterized regulators of OP migration. The current study hypothesizes that PDGF-A and FGF2 regulate the migration of OP through transient activation of the extracellular signal-regulated protein kinase (ERK) signaling pathway. The results show that activation of ERK is required for OP migration. It also demonstrates the significance of threshold levels of growth factors and temporal regulation for OP migration. Furthermore, the chemokine CXCL1 has been shown to play a critical role in regulating the dispersal of OP during development, although the mechanisms underlying this regulation are unknown. Previous studies have shown that calcium flux is required for OP migration. CXCL1 induces calcium flux in cells; therefore we hypothesized that CXCL1 inhibition of OP migration was regulated via changes in intracellular calcium flux. However, our results show that CXCL1 inhibition of OP migration is independent of calcium signaling. In addition, we show that CXCL1 inhibition of OP migration is specific to PDGF-A induced migration. Lastly, the current study identifies a transcriptional regulator, methyl-CpG-binding protein 2 (MeCP2) as regulating the expression of myelin specific genes in a transgenic mouse. Interestingly, gene expression of myelin associated proteins myelin basic protein (MBP), myelin associated glycoprotein (MAG)and proteolipid protein (PLP), which play an important role in regulation of OL differentiation and subsequent formation of myelin of the myelin sheath, where found to be dysregulated. Overall, these findings reveal previously unknown roles of various intrinsic factors in successive phases of OL development. It aims to provide a better understanding of complexity to myelin development, function and disease.