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 (RXR gamma) 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 RXR gamma, MBP and phosphatidylinositol 4,5-bisphosphate (PIP2) levels, maximizes synthetic axon engagement. Conversely, RXR gamma gene silencing reduces the ability of the drugs to promote MBP expression. This work provides a view of how EGFR/ErbB inhibition controls OPC differentiation and indicates the combination of Clobetasol and Gefitinib as a potent remyelination-enhancing treatment.

Nocita, E., Del Giovane, A., Tiberi, M., Boccuni, L., Fiorelli, D., Sposato, C., et al. (2019). EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP. CELLS, 8(8), 844 [10.3390/cells8080844].

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

NOCITA, EMANUELA;Romano, Elena;Rainer, Alberto;Traversa, Enrico;Ragnini, Antonella
2019-08-06

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 (RXR gamma) 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 RXR gamma, MBP and phosphatidylinositol 4,5-bisphosphate (PIP2) levels, maximizes synthetic axon engagement. Conversely, RXR gamma gene silencing reduces the ability of the drugs to promote MBP expression. This work provides a view of how EGFR/ErbB inhibition controls OPC differentiation and indicates the combination of Clobetasol and Gefitinib as a potent remyelination-enhancing treatment.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10
English
Con Impact Factor ISI
EGFR inhibitor; drug screening; microfibers; remyelination; smoothened agonist
L'autore Ragnini A ha usato nella pubblicazione il nome Ragnini-Wilson A
https://www.mdpi.com/2073-4409/8/8/844
Nocita, E., Del Giovane, A., Tiberi, M., Boccuni, L., Fiorelli, D., Sposato, C., et al. (2019). EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP. CELLS, 8(8), 844 [10.3390/cells8080844].
Nocita, E; Del Giovane, A; Tiberi, M; Boccuni, L; Fiorelli, D; Sposato, C; Romano, E; Basoli, F; Trombetta, M; Rainer, A; Traversa, E; Ragnini, A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/220284
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