Repression of phospho-JNK and infarct volume in ischemic brain of JIP1-deficient mice.
Mice lacking JIP1, a scaffold protein that organizes JNK pathway components, were constructed independently by two groups. The proposed in vivo function, however, remains contradictory; One study reported that targeted disruption of the jip1 caused embryonic death due to the requirement of JIP1 for fertilized eggs (Thompson et al. [2001] J. Biol. Chem. 276:27745-27748). In contrast, another group (Whitmarsh et al. [2001] Genes Dev. 15:2421-2432) demonstrated that JIP1-deficient mice were viable and that the JIP1 null mutation inhibited the kainic acid-induced JNK activation and neuronal death. The current study was undertaken to re-elucidate the in vivo roles of JIP1 using newly generated JIP1 knockout mice. Our JIP1-deficient mice were viable and healthy. The transient focal ischemic insult produced by middle cerebral artery occlusion (MCAO) strongly activated JNK in brain of jip1(+/+), jip1(+/-), and jip1(-/-) mice. Increased JNK activity was sustained for more than 22 hr in jip1(+/+) and jip1(+/-), whereas it was repressed rapidly in jip1(-/-). Concomitantly, the infarct volume produced by the ischemic insult in jip1(-/-) was reduced notably compared to that in jip1(+/+) brain. These results suggest that JIP1 plays a pivotal role in regulating the maintenance of phosphorylated JNK and neuronal survival in postischemic brain, but is not essential for JNK activation and early development.
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D020520:Brain Infarction / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002545:Brain Ischemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D015854:Up-Regulation / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C490665:Mapk8ip protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases