title: Egr-1 is a critical regulator of EGF-receptor-mediated expansion of subventricular zone neural stem cells and progenitors during recovery from hypoxia-hypoglycemia.
abstract: We recently established that the EGF-R (epidermal growth factor receptor) (EGF-R) is an essential regulator of the reactive expansion of SVZ (subventricular zone) NPs (neural precursors) that occurs during recovery from hypoxic-ischemic brain injury. The purpose of the current studies was to identify the conditions and the transcription factor (s) responsible for inducing the EGF-R. Here, we show that the increase in EGF-R expression and the more rapid division of the NPs can be recapitulated in in vitro by exposing SVZ NPs to hypoxia and hypoglycemia simultaneously, but not separately. The EGF-R promoter has binding sites for multiple transcription factors that includes the zinc finger transcription factor, Egr-1. We show that Egr-1 expression increases in NPs, but not astrocytes, following hypoxia and hypoglycemia where it accumulates in the nucleus. To determine whether Egr-1 is necessary for EGF-R expression, we used SiRNAs (small interfering RNA) specific for Egr-1 to decrease Egr-1 expression. Knocking-down Egr-1 decreased basal levels of EGF-R and it abolished the stress-induced increase in EGF-R expression. By contrast, HIF-1 accumulation did not contribute to EGF-R expression and FGF-2 only modestly induced EGF-R. These studies establish a new role for Egr-1 in regulating the expression of the mitogenic EGF-R. They also provide new information into mechanisms that promote NP expansion and provide insights into strategies for amplifying the numbers of stem cells for CNS (central nervous system) regeneration.
authors.affiliation: Department of Neurology and Neuroscience, University Hospital Cancer Center, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Dhivyaa
authors.initials: D
authors.lastname: Alagappan
authors.forename: Murugabaskar
authors.initials: M
authors.lastname: Balan
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Jiang
authors.forename: Rachel B
authors.initials: RB
authors.lastname: Cohen
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Kotenko
authors.forename: Steven W
authors.initials: SW
authors.lastname: Levison
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism / Q000502:physiology; D051766:Early Growth Response Protein 1 / Q000502:physiology*; D066246:ErbB Receptors / Q000502:physiology*; D007003:Hypoglycemia / Q000473:pathology*; D002534:Hypoxia, Brain / Q000473:pathology*; D007150:Immunohistochemistry; D058953:Neural Stem Cells / Q000502:physiology*; D016133:Polymerase Chain Reaction; D061251:Primary Cell Culture; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D013312:Stress, Physiological; D014162:Transfection; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D012313:RNA; D066246:ErbB Receptors