Attenuation of Notch signaling promotes the differentiation of neural progenitors into neurons in the hippocampal CA1 region after ischemic injury.
Intercellular signaling via cell-surface Notch receptors controls the cell-fate decision in the developing brain. Recent studies have suggested that the response of endogenous neural stem cells to brain injury in adult mammals might be mediated by Notch signaling. Here, we investigated the role of Notch signaling in ischemic damage in the hippocampal CA1 region after transient global ischemia in rats. In the acute phase of ischemia, Notch1-positive cells increased in number in the posterior periventricle, which is the posterior part of the lateral ventricle, after the i.c.v. administration of epidermal growth factor and fibroblast growth factor-2. In addition, Notch signaling was upregulated in the CA1 region 5 days after ischemia. By contrast, the attenuation of Notch signaling caused by the administration of a gamma-secretase inhibitor in the subacute phase (6-12 days after ischemia) amplified the immature migratory neurons 12 days after ischemia, and resulted in an increased number of newly generated neurons in the CA1 after 28 days. Our results suggest that Notch signaling in the CA1 is activated in parallel with the increase of endogenous neural stem cells stimulated by ischemia, and that the attenuation of Notch signaling could induce more efficient differentiation of neural progenitors toward a neuronal lineage.
Oya
S
S
Department of Neurosurgery, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Yoshikawa
G
G
Takai
K
K
Tanaka
J-I
JI
Higashiyama
S
S
Saito
N
N
Kirino
T
T
Kawahara
N
N
D053687:Adult Stem Cells / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000008:administration & dosage; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage; D006624:Hippocampus / Q000473:pathology*; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology* / Q000628:therapy; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D000089622:Doublecortin Domain Proteins; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D051880:Receptors, Notch; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine