Egr1 maintains NSC proliferation and its overexpression counteracts cell cycle exit triggered by the withdrawal of Epidermal Growth Factor

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 signalling pathways that regulate NSCs proliferation and differentiation remain poorly understood. The early growth response gene 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 EGF/EGFR signaling pathway. We also show that Egr-1 over-expression 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 NSCs proliferation, such as cell cycle regulators, cyclins and cyclin-dependent kinase inhibitors.