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Review
. 2020 Aug 12;9(8):1887.
doi: 10.3390/cells9081887.

Role of EGFR in the Nervous System

Roberta Romano  1 , Cecilia Bucci  1
Affiliations
Review

Role of EGFR in the Nervous System

Roberta Romano et al. Cells. .

Abstract

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.

Keywords: EGF; EGFR; brain; central nervous system; neurodegenerative disease; neurons; peripheral nervous system.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Representation of the four ErbB receptors and their ligands. EGF: epidermal growth factor; TGF-α: transforming growth factor-α; HB-EGF: heparin-binding EGF.
Figure 2
Figure 2
Intracellular fate of epidermal growth factor receptor (EGFR) after its activation. (A) When EGF is poorly concentrated, EGFR undergoes a low activation and it is subjected to clathrin-mediate endocytosis. The receptor reaches the early endosomes and tyrosine-protein phosphatase non-receptor 1 (PTP1B), which resides in the ER, dephosphorylates EGFR at the contact sites between ER and early endosomes. Then, EGFR is recycled back to the plasma membrane in RAB11-positive vesicles. (B) When EGF concentration is high, EGFR is more activated, and it is internalized through clathrin-independent endocytosis. After ubiquitination EGFR, reaches multivesicular bodies (MVBs) before being degraded into lysosomes.
Figure 3
Figure 3
Diagram representing what happens to the nervous system cells after EGFR ablation. At P0, EGFR is widely expressed in the nervous system. EGFR deletion is detrimental for progenitors, astrocytes, oligodendrocytes and neurons. SVZ: subventricular zone; OPCs: oligodendrocyte precursor cells; PNS: peripheral nervous system; CNS: central nervous system; GFAP: glial fibrillary acid protein; DRG: dorsal root ganglia.
Figure 4
Figure 4
EGFR regulates neural stem cells and progenitors. (A) Neural stem cells can grow in vitro as neurospheres. These clonal aggregates can differentiate into oligodendrocytes, neurons or astrocytes if they express EGFR while, following EGFR ablation, they can differentiate only into astrocytes. (B) Following cell-cell interaction, EGFR activation in neural progenitor cells (NPCs) stimulates Notch1 ubiquitination and degradation in adult neural stem cells (NSCs). This mechanism is responsible for NPC pool enlargement at the expense of NSC proliferation. (C) In the VZ, NPCs expressing high EGFR levels can undergo asymmetric mitosis producing a daughter cell expressing low EGFR levels which continues to proliferate and a daughter cell expressing high EGFR levels which migrates in the SVZ. Here, it can divide asymmetrically producing a daughter cell with high EGFR levels that differentiates into astrocyte and a daughter cell with low EGFR levels that enters in a diverse differentiation path.
Figure 5
Figure 5
EGFR regulate astrocyte morphology. (A) Mature astrocytes show cribriform structures which surround axons sustaining neuronal functions. EGFR signaling stimulates the acquisition of these processes. (B) EGFR blockade during CNS development inhibits the formation of astrocytes’ processes leading to neuronal degeneration.
Figure 6
Figure 6
EGFR regulates oligodendrogenesis and neurite outgrowth. (A) EGFR overexpression stimulates oligodendrocyte precursor cells to differentiate into myelinating oligodendrocytes, highlighting its important role in oligodendrogenesis. (B) Axon engagement, which represents the final step of oligodendrocytes maturation, is stimulate by EGFR inhibition. (C) Microglia in the corpus callosum produce chitinase-3-like-3 which activates EGFR expressed by NSCs in the near SVZ. This leads to MEK/ERK pathway activation that promotes oligodendrogenesis. (D) EGFR activates AKT and ERK signaling pathways which are important for neurite outgrowth.
Figure 7
Figure 7
EGFR is associated with neurodegenerative diseases. (A) Postmortem brains of patients with Parkinson’s disease show reduced expression of EGF and EGFR. Wild-type parkin sustains EGFR signaling while parkin’s mutations, which are associated with a recessive form of Parkinson’s disease, lead to increased EGFR degradation. (B) Aged APP/PS1 double transgenic mice that show plaque formation and memory loss, the hallmarks of Alzheimer’s disease, have reduced EGFR expression that can contribute to neurodegeneration. (C) EGFR mRNA is overexpressed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients.
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