Neonatal stroke in mice causes long-term changes in neuronal Notch-2 expression that may contribute to prolonged injury.
OBJECTIVE
Notch receptors (1-4) are membrane proteins that, on ligand stilumation, release their cytoplasmic domains to serve as transcription factors. Notch-2 promotes proliferation both during development and cancer, but its role in response to ischemic injury is less well understood. The purpose of this study was to understand whether Notch-2 is induced after neonatal stroke and to investigate its functional relevance.


METHODS
P12 CD1 mice were subjected to permanent unilateral (right-sided) double ligation of the common carotid artery.


RESULTS
Neonatal ischemia induces a progressive brain injury with prolonged apoptosis and Notch-2 up-regulation. Notch-2 expression was induced shortly after injury in hippocampal areas with elevated c-fos activation and increased cell death. Long-term induction of Notch-2 also occurred in CA1 and CA3 in and around areas of cell death, and had a distinct pattern of expression as compared to Notch-1. In vitro oxygen glucose deprivation treatment showed a similar increase in Notch-2 in apoptotic cells. In vitro gain of function experiments, using an active form of Notch-2, show that Notch-2 induction is neurotoxic to a comparable extent as oxygen glucose deprivation treatment.


CONCLUSIONS
These results suggest that Notch-2 up-regulation after neonatal ischemia is detrimental to neuronal survival.
Albéri
Lavinia
L
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lavinia.alberi@unifr.ch
Chi
Zhikai
Z
Kadam
Shilpa D
SD
Mulholland
Justin D
JD
Dawson
Valina L
VL
Gaiano
Nicholas
N
Comi
Anne M
AM
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D015153:Blotting, Western; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051883:Receptor, Notch2 / Q000378:metabolism*; D020521:Stroke / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D015854:Up-Regulation
C497765:Notch2 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D051883:Receptor, Notch2