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

Nocita, Emanuela; Giovane, Alice Del; Tiberi, Marta; Boccuni, Laura; Fiorelli, Denise; Sposato, Carola; Romano, Elena; Basoli, Francesco; Trombetta, Marcella; Rainer, Alberto; Traversa, Enrico; Ragnini-Wilson, Antonella

doi:10.3390/cells8080844

Cited by 11 publications

(43 citation statements)

References 69 publications

(147 reference statements)

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“…While oligodendrogenesis requires the upregulation of EGFR signaling, the final step of oligodendrocytes maturation, that is axon engagement, is fostered by EGFR inhibition ( Figure 6 B). In fact, it was demonstrated that EGFR inhibition stimulates MBP expression in premyelinating oligodendrocytes and cotreatment with Clobetasol and Gefitinib, which inhibit EGFR, favors MBP expression and localization of phosphatidylinositol 4,5-bisphosphate (PIP2) in endosome-like structures leading to membrane expansion and, consequently, to axon engagement [ 99 ].…”

Section: Egfr Functions In the Cnsmentioning

confidence: 99%

Role of EGFR in the Nervous System

Romanò

Bucci

2020

Cells

103

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Epidermal growth factor receptor (EGFR) is the first discovered member of the receptor tyrosine kinase superfamily and plays a fundamental role during embryogenesis and in adult tissues, being involved in growth, differentiation, maintenance and repair of various tissues and organs. The role of EGFR in the regulation of tissue development and homeostasis has been thoroughly investigated and it has also been demonstrated that EGFR is a driver of tumorigenesis. In the nervous system, other growth factors, and thus other receptors, are important for growth, differentiation and repair of the tissue, namely neurotrophins and neurotrophins receptors. For this reason, for a long time, the role of EGFR in the nervous system has been underestimated and poorly investigated. However, EGFR is expressed both in the central and peripheral nervous systems and it has been demonstrated to have specific important neurotrophic functions, in particular in the central nervous system. This review discusses the role of EGFR in regulating differentiation and functions of neurons and neuroglia. Furthermore, its involvement in regeneration after injury and in the onset of neurodegenerative diseases is examined.

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Section: Egfr Functions In the Cnsmentioning

confidence: 99%

Role of EGFR in the Nervous System

Romanò

Bucci

2020

Cells

103

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“…Mice that lack RxRγ fail in adult oligodendrogenesis [38]. Consistent with this finding, many of the promyelinating drugs isolated in phenotypical screens upregulate both MBP expression and RxRγ [33,37]. Using purified primary OPCs isolated from control and OPC-specific Chd7-deficient mice, it has been shown that TFs such as Sox10, Olig2, Nkx2.2, and Ascl1 are key regulators of OL differentiation by directly controlling transcription of genes implicated in chromatin remodeling.…”

Section: Molecular Aspects Of Opc Differentiation In Murine Models Ofmentioning

confidence: 77%

“…Here, we review the main contributions that have led to the current state-of-the-art of in vitro models, drug screening, and validation studies. Although at the moment it is early to evaluate how these findings will impact clinical therapies ( Table 1 and Table 2 ), they have provided a wealth of knowledge on the mechanisms of adult CNS remyelination [ 1 , 4 , 6 , 7 , 9 , 37 ]. Furthermore, we discuss recent biological findings in the CNS remyelination process, as we think new drug discovery programs will have to focus on recent advances in the molecular understanding of OPC differentiation in man compared to murine models.…”

Section: Introductionmentioning

confidence: 99%

The Current Challenges for Drug Discovery in CNS Remyelination

Balestri

Giovane

Sposato

et al. 2021

IJMS

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The myelin sheath wraps around axons, allowing saltatory currents to be transmitted along neurons. Several genetic, viral, or environmental factors can damage the central nervous system (CNS) myelin sheath during life. Unless the myelin sheath is repaired, these insults will lead to neurodegeneration. Remyelination occurs spontaneously upon myelin injury in healthy individuals but can fail in several demyelination pathologies or as a consequence of aging. Thus, pharmacological intervention that promotes CNS remyelination could have a major impact on patient’s lives by delaying or even preventing neurodegeneration. Drugs promoting CNS remyelination in animal models have been identified recently, mostly as a result of repurposing phenotypical screening campaigns that used novel oligodendrocyte cellular models. Although none of these have as yet arrived in the clinic, promising candidates are on the way. Many questions remain. Among the most relevant is the question if there is a time window when remyelination drugs should be administrated and why adult remyelination fails in many neurodegenerative pathologies. Moreover, a significant challenge in the field is how to reconstitute the oligodendrocyte/axon interaction environment representative of healthy as well as disease microenvironments in drug screening campaigns, so that drugs can be screened in the most appropriate disease-relevant conditions. Here we will provide an overview of how the field of in vitro models developed over recent years and recent biological findings about how oligodendrocytes mature after reactivation of their staminal niche. These data have posed novel questions and opened new views about how the adult brain is repaired after myelin injury and we will discuss how these new findings might change future drug screening campaigns for CNS regenerative drugs.

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“…Clobetasol acts as a Smoothened (Smo) agonist to upregulate myelin gene expression in the Oli-neuM cell line, and RxRγ activation is required for MBP expression after clobetasol treatment [25]. RXRγ upregulation due to clobetasol treatment may contribute to coordinating the lipid metabolism with MBP expression under EGFR and Smo signaling in myelinating OL [26]. As a corticosteroid, clobetasol can modulate glucocorticoid receptor signaling in the cytoplasm of cells.…”

Section: Discussionmentioning

confidence: 99%

Clobetasol Attenuates White Matter Injury by Promoting Oligodendrocyte Precursor Cell Differentiation

Yuan

Bai

et al. 2020

Pediatr Neurosurg

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Introduction: White matter injury (WMI) is the most common brain injury in preterm infants and can result in life-long neurological deficits. The main cause of WMI is damage to the oligodendrocyte precursor cells (OPC) in the brain that results in delayed myelin sheath formation, or the destruction of existing myelin sheaths. OPC undergo highly regulated and strictly timed developmental changes that result in their transformation to mature oligodendrocytes capable of myelin production. Objective: Studies have shown that clobetasol strongly promotes differentiation of OPC into myelin sheaths. Therefore, we hypothesized that clobetasol may be a therapeutic option for the treatment of preterm WMI. Methods: We induced a WMI rat model and observed white matter damage under an optical microscope. Rats subjected to WMI were injected intraperitoneally with clobetasol (2 or 5 mg/kg daily) from day 1 to day 5 in the early treatment groups, or from day 6 to day 10 in the late treatment groups. After 17 days, the rats were sacrificed and the expression of myelin basic protein (MBP) was visualized using immunofluorescence. In addition, we evaluated myelin sheath formation using electron microscopy. The rats were also subjected to the suspension test, ramp test, and open field test to evaluate neurobehavioral functions. Results: A rat model of WMI was successfully induced. It was found that clobetasol significantly induced MBP expression and myelin sheath formation and improved neurobehavioral function in the rats subjected to WMI. Conclusions: Our results indicate that clobetasol attenuates WMI by promoting OPC differentiation, and it may be an effective therapeutic agent for the treatment of preterm WMI.

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

Cited by 11 publications

References 69 publications

Role of EGFR in the Nervous System

Role of EGFR in the Nervous System

The Current Challenges for Drug Discovery in CNS Remyelination

Clobetasol Attenuates White Matter Injury by Promoting Oligodendrocyte Precursor Cell Differentiation

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