EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP

Cells
Emanuela NocitaAntonella Ragnini-Wilson

Abstract

Remyelination in the adult brain relies on the reactivation of the Neuronal Precursor Cell (NPC) niche and differentiation into Oligodendrocyte Precursor Cells (OPCs) as well as on OPC maturation into myelinating oligodendrocytes (OLs). These two distinct phases in OL development are defined by transcriptional and morphological changes. How this differentiation program is controlled remains unclear. We used two drugs that stimulate myelin basic protein (MBP) expression (Clobetasol and Gefitinib) alone or combined with epidermal growth factor receptor (EGFR) or Retinoid X Receptor gamma (RXRγ) gene silencing to decode the receptor signaling required for OPC differentiation in myelinating OLs. Electrospun polystyrene (PS) microfibers were used as synthetic axons to study drug efficacy on fiber engagement. We show that EGFR inhibition per se stimulates MBP expression and increases Clobetasol efficacy in OPC differentiation. Consistent with this, Clobetasol and Gefitinib co-treatment, by co-regulating RXRγ, MBP and phosphatidylinositol 4,5-bisphosphate (PIP2) levels, maximizes synthetic axon engagement. Conversely, RXRγ gene silencing reduces the ability of the drugs to promote MBP expression. This work provides a view of how EGFR/...Continue Reading

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Citations

Aug 19, 2020·Cells·Roberta Romano, Cecilia Bucci
Apr 4, 2021·International Journal of Molecular Sciences·Sonia BalestriAntonella Ragnini-Wilson

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Methods Mentioned

BETA
PCR
Transfection
confocal microscopy

Software Mentioned

Leica Application Suite X
ImageJ
GraphPad Prism
GrahPad
LAS
Imaris
Scan R
X Matrix Screener
siScramble
Matrix Screener

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