Heparin-binding epidermal growth factor-like growth factor: hypoxia-inducible expression in vitro and stimulation of neurogenesis in vitro and in vivo.
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 approximately 50% in cortical cultures, where expression was associated with mature and immature neurons. HB-EGF (5-100 ng/ml) stimulated by approximately 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.
Jin
Kunlin
K
Buck Institute for Age Research, Novato, California 94945, USA.
Mao
Xiao Ou
XO
Sun
Yunjuan
Y
Xie
Lin
L
Jin
Lan
L
Nishi
Eiichiro
E
Klagsbrun
Michael
M
Greenberg
David A
DA
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000096:biosynthesis* / Q000494:pharmacology*; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017978:Receptors, Growth Factor / Q000032:analysis; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism
C587884:Hbegf protein, mouse; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D017978:Receptors, Growth Factor; D004815:Epidermal Growth Factor