Non-receptor tyrosine kinase Src is required for ischemia-stimulated neuronal cell proliferation via Raf/ERK/CREB activation in the dentate gyrus.
BACKGROUND
Neurogenesis in the adult mammalian hippocampus may contribute to repairing the brain after injury. However, Molecular mechanisms that regulate neuronal cell proliferation in the dentate gyrus (DG) following ischemic stroke insult are poorly understood. This study was designed to investigate the potential regulatory capacity of non-receptor tyrosine kinase Src on ischemia-stimulated cell proliferation in the adult DG and its underlying mechanism.


RESULTS
Src kinase activated continuously in the DG 24 h and 72 h after transient global ischemia, while SU6656, the Src kinase inhibitor significantly decreased the number of bromodeoxyuridine (BrdU) labeling-positive cells of rats 7 days after cerebral ischemia in the DG, as well as down-regulated Raf phosphorylation at Tyr(340/341) site, and its down-stream signaling molecules ERK and CREB expression followed by 24 h and 72 h of reperfusion, suggesting a role of Src kinase as an enhancer on neuronal cell proliferation in the DG via modifying the Raf/ERK/CREB cascade. This hypothesis is supported by further findings that U0126, the ERK inhibitor, induced a reduction of adult hippocampal progenitor cells in DG after cerebral ischemia and down-regulated phospho-ERK and phospho-CREB expression, but no effect was detected on the activities of Src and Raf.


CONCLUSIONS
Src kinase increase numbers of newborn neuronal cells in the DG via the activation of Raf/ERK/CREB signaling cascade after cerebral ischemia.
Tian
He-Ping
HP
Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. grantnw@163.com
Huang
Bao-Sheng
BS
Zhao
Jie
J
Hu
Xiao-Han
XH
Guo
Jun
J
Li
Li-Xin
LX
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D002070:Butadienes / Q000494:pharmacology; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D048490:raf Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D002070:Butadienes; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D007211:Indoles; D009570:Nitriles; C416927:SU 6656; D013449:Sulfonamides; C113580:U 0126; D019061:src-Family Kinases; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases