Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene

Abstract

Excitatory amino acids induce both acute membrane depolarization and latent cellular toxicity, which often leads to apoptosis in many neurological disorders. Recent studies indicate that glutamate toxicity may involve the c-Jun amino-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases. One member of the JNK family, Jnk3, may be required for stress-induced neuronal apoptosis, as it is selectively expressed in the nervous system. Here we report that disruption of the gene encoding Jnk3 in mice caused the mice to be resistant to the excitotoxic glutamate-receptor agonist kainic acid: they showed a reduction in seizure activity and hippocampal neuron apoptosis was prevented. Although application of kainic acid imposed the same level of noxious stress, the phosphorylation of c-Jun and the transcriptional activity of the AP-1 transcription factor complex were markedly reduced in the mutant mice. These data indicate that the observed neuroprotection is due to the extinction of a Jnk3-mediated signalling pathway, which is an important component in the pathogenesis of glutamate neurotoxicity.

Impaired neural stem cell expansion and hypersensitivity to epileptic seizures in mice lacking the EGFR in the brain

“…One model routinely used to investigate such phenomenon is the triggering of seizures with Kainic acid (KA), a marine‐derived amino acid that has a very high activating potential of glutamate transporters 38, 39, 40, 41. Several molecules acting downstream of the EGFR have been implicated in mediating KA‐induced neurotoxicity 42, 43. KA elicits seizures by direct stimulation of glutamate receptors, and indirectly by increasing the release of excitatory amino acids from nerve terminals 40.…”

Diverse functions of JNK signaling and c-Jun in stress response and apoptosis

“…Even in the complete absence of c-Fos and c-Jun in double knockout mouse embryos, no defects in the normally occurring developmentally programmed cell death were recorded (Ro er-Tarlov et al, 1996). Consistently, mutant mice de®cient in either the jnk1, jnk2, or jnk3 genes are viable and develop normally (Dong et al, 1998;Yang et al, 1997b;. However, in a recent study, in which dual JNK knockouts were generated, it was found that the dual de®ciency of JNK1 and JNK2 causes embryonic lethality due to severe dysregulation of apoptosis during brain development (Kuan et al, 1999).…”

“…In contrast, mutant mice lacking either JNK1, or JNK2, or JNK3 develop without obvious structural abnormalities. However, JNK1 as well as JNK2 mutant mice exhibit decreased activation-induced Tcell death and imbalance between T H 1 and T H 2 mediated immune responses (Dong et al, 1998;Sabapathy et al, 1999;Yang et al, 1997bYang et al, , 1998. In Drosophila, evidence has been presented for an involvement of Jun in several developmental processes.…”

“…The most conclusive evidence for the importance of JNK activation and c-Jun phosphorylation for neuronal apoptosis in the animal has been obtained in gene targeting experiments (Table 1). It was shown that deletion of brain-speci®c jnk3 gene, but not jnk1 or jnk2, causes protection of hippocampal neurons from kainate-induced apoptosis (Dong et al, 1998;Yang et al, 1997bYang et al, , 1998. Simultaneously, AP-1-dependent reporter activity, but not the activation of the c-fos and c-jun genes by kainate, is greatly reduced in the jnk3 mutant background, suggesting that the post-translational regulation of AP-1 activity by JNK3 is critical for the triggering of death.…”

Stress signals for apoptosis: ceramide and c-Jun kinase

“…The evidence that the JNK pathway is pro-apoptotic derives from studies that show that these kinases are activated rapidly in cells destined to undergo an apoptotic response, that their overexpression results in apoptosis in some cells, that anti-sense inhibition or the use of dominant negative constructs attenuates the apoptotic response, and in a recent publication by the use of a knock-out mouse Brenner et al, 1997;Butter®eld et al, 1997;Cardone et al, 1997;Chen et al, 1996a,b;Chuang et al, 1997;Frisch et al, 1996;Goillot et al, 1997;Seimiya et al, 1997;Verheij et al, 1996;Xia et al, 1995;Yang et al, 1997a;Zanke et al, 1996). In the latter studies, in mice de®cient in JNK3, which is restricted to the brain, there was a reduction in seizure activity and hippocampal apoptosis in response to the excitotoxic glutamate-receptor agonist kainic acid (Yang et al, 1997a).…”