EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP
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 tran...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-08-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/8/8/844 |
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| author | Emanuela Nocita Alice Del Giovane Marta Tiberi Laura Boccuni Denise Fiorelli Carola Sposato Elena Romano Francesco Basoli Marcella Trombetta Alberto Rainer Enrico Traversa Antonella Ragnini-Wilson |
| author_facet | Emanuela Nocita Alice Del Giovane Marta Tiberi Laura Boccuni Denise Fiorelli Carola Sposato Elena Romano Francesco Basoli Marcella Trombetta Alberto Rainer Enrico Traversa Antonella Ragnini-Wilson |
| author_sort | Emanuela Nocita |
| collection | DOAJ |
| description | 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/ErbB inhibition controls OPC differentiation and indicates the combination of Clobetasol and Gefitinib as a potent remyelination-enhancing treatment. |
| first_indexed | 2024-03-12T09:17:43Z |
| format | Article |
| id | doaj.art-24fd526a1c554a4ba46163efbaae0ba7 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T09:17:43Z |
| publishDate | 2019-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-24fd526a1c554a4ba46163efbaae0ba72023-09-02T14:42:23ZengMDPI AGCells2073-44092019-08-018884410.3390/cells8080844cells8080844EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBPEmanuela Nocita0Alice Del Giovane1Marta Tiberi2Laura Boccuni3Denise Fiorelli4Carola Sposato5Elena Romano6Francesco Basoli7Marcella Trombetta8Alberto Rainer9Enrico Traversa10Antonella Ragnini-Wilson11NeurotechIT Laboratory, Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyNeurotechIT Laboratory, Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyNeurotechIT Laboratory, Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyNeurotechIT Laboratory, Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyNeurotechIT Laboratory, Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyNeurotechIT Laboratory, Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyAdvanced Microscopy Center, Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyDepartment of Engineering, Università Campus Bio-Medico di Roma, 00128 Rome, ItalyDepartment of Engineering, Università Campus Bio-Medico di Roma, 00128 Rome, ItalyDepartment of Engineering, Università Campus Bio-Medico di Roma, 00128 Rome, ItalySchool of Materials and Energy, University of Electronic Science and Technology of China, Chengdu 611731, ChinaNeurotechIT Laboratory, Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, ItalyRemyelination 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/ErbB inhibition controls OPC differentiation and indicates the combination of Clobetasol and Gefitinib as a potent remyelination-enhancing treatment.https://www.mdpi.com/2073-4409/8/8/844remyelinationEGFR inhibitorsmoothened agonistmicrofibersdrug screening |
| spellingShingle | Emanuela Nocita Alice Del Giovane Marta Tiberi Laura Boccuni Denise Fiorelli Carola Sposato Elena Romano Francesco Basoli Marcella Trombetta Alberto Rainer Enrico Traversa Antonella Ragnini-Wilson EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP Cells remyelination EGFR inhibitor smoothened agonist microfibers drug screening |
| title | EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP |
| title_full | EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP |
| title_fullStr | EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP |
| title_full_unstemmed | EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP |
| title_short | EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP |
| title_sort | egfr erbb inhibition promotes opc maturation up to axon engagement by co regulating pip2 and mbp |
| topic | remyelination EGFR inhibitor smoothened agonist microfibers drug screening |
| url | https://www.mdpi.com/2073-4409/8/8/844 |
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