Egr-1 Maintains NSC Proliferation and Its Overexpression Counteracts Cell Cycle Exit Triggered by the Withdrawal of Epidermal Growth Factor

Abstract

In adult mammals, neural stem cells (NSCs) reside in specialized niches at the level of selected CNS regions, such as the subventricular zone (SVZ). The signaling pathways that reg­ulate NSC proliferation and differentiation remain poorly understood. Early growth response protein 1 (Egr-1) is an important transcription factor, widely studied in the adult mammalian brain, mediating the activation of target genes by a variety of extracellular stimuli. In our study, we aimed at testing how Egr-1 regulates adult NSCs derived from mouse SVZ and, in particular, the interplay between Egr-1 and the proliferative factor EGF. We demonstrate that Egr-1 expression in NSCs is induced by growth factor stimulation, and its level decreases after EGF deprivation or by using AG1478, an inhibitor of the EGF/EGFR signaling pathway. We also show that Egr-1 overexpression rescues the cell proliferation decrease observed either after EGF removal or upon treatment with AG1478, suggesting that Egr-1 works downstream of the EGF pathway. To better understand this mechanism, we investigated targets downstream of both the EGF pathway and Egr-1, and found that they regulate genes involved in NSC proliferation, such as cell cycle regulators, cyclins, and cyclin-dependent kinase inhibitors.

Extracellular Vesicle-Induced Differentiation of Neural Stem Progenitor Cells

“…NSPCs were obtained from E13.5 mouse embryonic spinal cord and adapted to cell cultures as previously described [8,29,30]. Cells were maintained in a medium referred to as the “Expansion Medium” consisting of basal medium (Dulbecco’s Modified Eagle’s Medium (DMEM)/F12, 1% penicillin/streptomycin, 0.1 M L-glutamine (Sigma-Aldrich, St. Louis, MO, USA), 23.8 mg/100 mL Hepes, 7.5% NaHCO3, 0.6% glucose), supplemented with 20 ng/mL human recombinant EGF (EGF; R and D Systems, Minneapolis, MN, USA), 10 ng/mL of basic fibroblast growth factor (bFGF; Peprotec, London, UK) and 1% N2 supplement.…”

miR‑let‑7c‑3p targeting on Egr‑1 contributes to the committed differentiation of leukemia cells into monocyte/macrophages

“…For example, in normal somatic cells, Egr-1 is in a dormant state and the expression level is very low or even not expressed in the normal state. However, when the cell is stimulated by some physical and chemical factors, the rapid activation of Egr-1 allows cells to enter the proliferation phase from the resting phase, which in turn leads to cell proliferation (22,23). In tumor cells, the role of Egr-1 is more complex and can be expressed as an oncogene or tumor suppressor gene in different types of tumor, for example, Egr-1 promotes the malignant behaviors of LC cells (24), circCSPP1-miR-520h-Egr-1 activation axis lead to the progression of prostate tumor (25), and Egr-1 as a potential oncogene that promotes cell proliferation and defines Egr-1 as a new molecular target in DLBCL non-Hodgkin lymphomar (26).…”

Epidermal Growth Factor in the CNS: A Beguiling Journey from Integrated Cell Biology to Multiple Sclerosis. An Extensive Translational Overview

“…Early growth response(Egr)-1 is localized in the nucleus at a relatively low level, but expressed at high levels in the NEUs of some CNS regions (Beckmann and Wilce 1997 ). When stimulated by appropriate growth factors such as EGF, NSCs proliferate by activating a multiple signal pathway, that includes the Ras-Raf-MEK (MAPK/ERK kinase) -ERK (extracellular signal-regulated protein kinase) cascade and is connected with the cell cycle (Gao et al 2014 ; Cera et al 2018 ). ERK activation modulates the expression of several transcription factors including Egr-1 (Cera et al 2018 ).…”

“…When stimulated by appropriate growth factors such as EGF, NSCs proliferate by activating a multiple signal pathway, that includes the Ras-Raf-MEK (MAPK/ERK kinase) -ERK (extracellular signal-regulated protein kinase) cascade and is connected with the cell cycle (Gao et al 2014 ; Cera et al 2018 ). ERK activation modulates the expression of several transcription factors including Egr-1 (Cera et al 2018 ). The induction of Egr-1 by EGF also requires activation of the MAPK (mitogen activated protein kinase) cascade (Mayer et al 2009 ).…”