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Review
. 2022 Mar 17:16:838007.
doi: 10.3389/fncel.2022.838007. eCollection 2022.

Epidermal Growth Factor Pathway in the Age-Related Decline of Oligodendrocyte Regeneration

Andrea D Rivera  1 , Kasum Azim  2 , Veronica Macchi  1 , Andrea Porzionato  1 , Arthur M Butt  3 , Raffaele De Caro  1
Affiliations
Review

Epidermal Growth Factor Pathway in the Age-Related Decline of Oligodendrocyte Regeneration

Andrea D Rivera et al. Front Cell Neurosci. .

Abstract

Oligodendrocytes (OLs) are specialized glial cells that myelinate CNS axons. OLs are generated throughout life from oligodendrocyte progenitor cells (OPCs) via a series of tightly controlled differentiation steps. Life-long myelination is essential for learning and to replace myelin lost in age-related pathologies such as Alzheimer's disease (AD) as well as white matter pathologies such as multiple sclerosis (MS). Notably, there is considerable myelin loss in the aging brain, which is accelerated in AD and underpins the failure of remyelination in secondary progressive MS. An important factor in age-related myelin loss is a marked decrease in the regenerative capacity of OPCs. In this review, we will contextualize recent advances in the key role of Epidermal Growth Factor (EGF) signaling in regulating multiple biological pathways in oligodendroglia that are dysregulated in aging.

Keywords: EGF; EGFR; ErbB; aging; myelin; oligodendrocyte; white matter.

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Conflict of interest statement

AR and AB are shareholders of Gliagenesis LTD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
EGF receptor signaling and resolving its dysregulation in aged oligodendroglial via protein-protein network analysis. (A) EGFR is a member of ERBB receptors that belong to the superfamily of Receptor Tyrosine Kinases (RTKs). The binding of ligands to EGFR induces conformational changes resulting in the receptor homo- or heterodimerization at the cell surface. Dimerization of the extracellular regions of EGFR cascades results in further conformational change at the cytoplasmic region of the receptor, leading to the activation of the catalytic domain. EGFR dimers trans-autophosphorylate on tyrosine residues in the cytoplasmic tail becoming binding sites for the recruitment of intracellular modulator for downstream signaling cascades. Recruitment of complexes containing GRB2 and SOS1 directly through GRB2 or indirectly through SHC1 promotes the activation of RAS/RAF/MAP kinase signaling. The binding of GRB2 and GAB1 to phosphorylated EGFR leads to the activation of PI3K/AKT signaling cascade. Finally, PLCγcan be recruited to the phosphorylated EGFR which, in turn, activates IP3/PKC signaling. Image generated from REACTOME “Signaling by EGFR” (https://reactome.org/PathwayBrowser/#/R-HSA-177929). (B) RNA-seq transcriptome analysis of the aging murine brain was compared to a database of genes expressed by myelinating OLs (MOL) and 251 genes were identified as significantly altered in aging (Rivera et al., 2021b). (B) Functional protein-protein network analysis identified EGFR as centrally connected with ERBB3, NRAS, VCL, GSN, CLDN11, and the myelination node (yellow circles). Red nodes represent genes associated with Metabolism (p < 0.000034) and blue nodes represent genes associated with Myelination (p < 5.55e-07). PPI enrichment p-value < : 2.44e-15. Adapted from Rivera et al. (2021b).
Figure 2
Figure 2
Identification of altered EGFR signaling in aged myelinating oligodendrocytes are further associated as altered genes in Alzheimer’s disease and multiple sclerosis. The aging myelinating OLtranscriptome was interrogated to identify novel associations within disease-specific databases for Alzheimer’s disease and multiple sclerosis. Functional protein–protein prediction analysis identified EGFR at the core of the networks for Alzheimer’s disease and multiple sclerosis (PPI enrichment p < 0.0001).
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