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The Journal of Neuroscience, July 1, 2002, 22(13):5365-5373

Heparin-Binding Epidermal Growth Factor-Like Growth Factor: Hypoxia-Inducible Expression In Vitro and Stimulation of Neurogenesis In Vitro and In Vivo

Kunlin Jin¹, Xiao Ou Mao¹, Yunjuan Sun¹, Lin Xie¹, Lan Jin¹, Eiichiro Nishi², Michael Klagsbrun², and David A. Greenberg¹

¹ Buck Institute for Age Research, Novato, California 94945, and ² Departments of Surgical Research and Pathology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115

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.

Key words: neurogenesis; hypoxia; ischemia; heparin-binding epidermal growth factor-like growth factor (HB-EGF); epidermal growth factor receptor (EGFR/ErbB1); N-arginine dibasic convertase (NRDc)

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22135365-09$05.00/0

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