The role of EGFR and ErbB family related proteins in the oligodendrocyte specification in germinal niches of the adult mammalian brain

Abstract

In the adult brain, multipotent progenitor cells have been identified in three areas: the ventricular-subventricular zone (VZ-SVZ), adjacent to the striatal wall of the lateral ventricles, the subgranular zone (SGZ), located at the dentate gyrus of the hippocampus and the subcallosal zone (SCZ), located between the corpus callosum and the CA1 and CA2 regions of the hippocampus. The neural progenitor cells of these regions express the epidermal growth factor receptor (EGFR, ErbB-1 or HER1). EGF, the most important ligand for the EGFR, is a potent mitogenic agent that stimulates proliferation, survival, migration and differentiation into the oligodendrocyte lineage. Other ErbB receptors also activate several intracellular pathways for oligodendrocyte specification, migration and survival. However, the specific downstream pathways related to oligodendrogenesis and the hierarchic interaction among intracellular signaling cascades is not well-known. We summarize the current data regarding the role of EGFR and ErbB family signaling on neural stem cells and the downstream cascades involved in oligodendrogenesis in the neurogenic niches of the adult brain. Understanding the mechanisms that regulate proliferation, differentiation, migration of oligodendrocytes and myelination is of critical importance for the field of neurobiology and constitutes a crucial step in the design of stem-cell-based therapies for demyelinating diseases.

Long-term hydrocephalus alters the cytoarchitecture of the adult subventricular zone

“…The adult SVZ is a source of oligodendrocyte progenitor cells that partially help preserve the oligodendrocyte population in neighboring white matter regions (Galvez-Contreras et al, 2013; Gonzalez-Perez and Alvarez-Buylla, 2011; Menn et al, 2006). In our study, patients with chronic hydrocephalus by aqueductal stenosis showed a significant reduction in the width of the SVZ niche and the white matter regions (internal capsule and corpus callosum).…”

Novel subventricular zone early progenitor cell-specific adenovirus for in vivo therapy of central nervous system disorders reinforces brain stem cell heterogeneity

“…This area comprehends different neural cell types depending on their activation status and molecular diversity (Giachino et al 2013;Merkle et al 2007). The cellular basis for the current model of SVZ neurogenesis consists of a threetype cellular model (Doetsch 2003;Galvez-Contreras et al 2013) adjacent to an ependymal cell layer lining the lateral ventricle of the brain parenchyma. The type B NSCs express markers for epidermal growth factor receptor (EGFR), glial fibrillary acidic protein (GFAP), and nestin.…”

Epidermal growth factor, from gene organization to bedside

“…The receptor dimerization is a critical step for the activation of intrinsic tyrosine kinases and autophosphorylation of the c-terminal specific tyrosine-containing residues that serve as docking sites for a variety of signaling molecules harboring Src homology 2 (SH2) or phosphotyrosine binding (PTB) motifs, whose recruitments lead to the activation of Ras/Raf/MEK/ERK, JAK/STAT, PI3K/AKT/mTOR, and PLCγ/PKC signaling pathways that affect cell proliferation, differentiation, and apoptosis and consequently regulate many physiological processes, such as organ development, growth, regeneration, ion transportation, etc. [4,14,59–61]. …”

“…[144]. The expression levels of EGF and EGFR are correlated with progressive tumor growth and metastasis [59,145–147] through: 1) increasing tumor cell proliferation and migration through EGFR-Ras/Raf/MEK/ERK and EGFR-PI3K/AKT pathways [146]; 2) localization of EGFR to the nucleus to promote cell proliferation through its tyrosine kinase activity or by acting as a transcriptional regulator [144,146,148]; 3) dysregulation of autophage activity [149,150]; 4) stimulation by EGF of the expression of several matrix metalloproteinases (MMPs, such as MMP1 and MMP9) that facilitate cancer invasion and metastasis; and/or 5) EGF-mediated decrease in the abundance of microRNAs that restrain oncogenic transcription factors [151]. Therefore, specific EGFR inhibition is one of the key targets for cancer therapy.…”