Heparin-binding epidermal growth factor-like growth factor: Hypoxia-inducible expression in vitro and stimulation of neurogenesis in vitro and in vivo

Kunlin Jin, Xiao Ou Mao, Yunjuan Sun, Lin Xie, Lan Jin, Eiichiro Nishi, Michael Klagsbrun, David A. Greenberg

Research output: Contribution to journalArticle

165 Scopus citations

Abstract

Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is found in cerebral neurons, and its expression is increased after hypoxic or ischemic injury, which also stimulates neurogenesis. To investigate the possible role of HB-EGF in hypoxic-ischemic induction of neurogenesis, we measured its expression, effects, and target receptors in embryonic murine cerebral cortical cultures and in adult rat brain. Hypoxia increased HB-EGF expression by ∼50% in cortical cultures, where expression was associated with mature and immature neurons. HB-EGF (5-100 ng/ml) stimulated by ∼80% the incorporation of bromodeoxyuridine (BrdU) into cultured cells that expressed the HB-EGF receptors epidermal growth factor receptor (EGFR)/avian erythroblastic leukemia viral oncogene homolog 1 (ErbB1) and N-arginine dibasic convertase (NRDc). Intracerebroventricular administration of HB-EGF in adult rats increased BrdU labeling in the subventricular zone and in the subgranular zone of dentate gyrus, where EGFR/ErbB1 and NRDc were also expressed and where ischemia-induced neurogenesis is observed. We conclude that HB-EGF stimulates neurogenesis in proliferative zones of the adult brain that are also affected in ischemia and that it does so by interacting with EGFR/ErbB1 and possibly NRDc. Therefore, HB-EGF may help to trigger proliferation of neuronal precursors in brain after hypoxic or ischemic injury.

Original languageEnglish
Pages (from-to)5365-5373
Number of pages9
JournalJournal of Neuroscience
Volume22
Issue number13
DOIs
StatePublished - 1 Jul 2002

Keywords

  • Epidermal growth factor receptor (EGFR/ErbB1)
  • Heparin-binding epidermal growth factor-like growth factor (HB-EGF)
  • Hypoxia
  • Ischemia
  • N-arginine dibasic convertase (NRDc)
  • Neurogenesis

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