Repression of phospho‐JNK and infarct volume in ischemic brain of JIP1‐deficient mice

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Abstract
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.