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

Nature volume 389, pages 865–870 (1997)Cite this article

Abstract

Excitatory amino acids induce both acute membrane depolarization and latent cellular toxicity, which often leads to apoptosis in many neurological disorders1,2. Recent studies indicate that glutamate toxicity may involve the c-Jun amino-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases3,4,5. One member of the JNK family, Jnk3, may be required for stress-induced neuronal apoptosis, as it is selectively expressed in the nervous system6,7. 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 animportant component in the pathogenesis of glutamate neurotoxicity.

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Figure 1: Generation of Jnk3-deficient mice by homologous recombination.
Figure 2: Generation of Jnk3-deficient mice by homologous recombination.
Figure 3: Comparison of seizure responses in littermates of varied Jnk3 genotype.
Figure 4: Comparison of seizure responses in littermates of varied Jnk3 genotype.
Figure 5: Comparison of kainic acid-induced expression of c-Fos, c-Jun and phosphorylated c-Jun in wild-type and Jnk3(−/−) mice.
Figure 6: Kainic acid-induced AP-1 transcriptional activity in wild-type (+/+) and Jnk3 knockout (−/−) mice expressing the AP-1 luciferase reporter transgene.
Figure 7: Comparison of kainic acid-induced cell damage in the hippocampus in wild-type and Jnk3 knockout mice.

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Acknowledgements

This Letter is dedicated to the memory of Morton Nathanson, who suggested key experiments. We thank S. Benzer, D. Y. Loh, C. A. Miller, J. I. Morgan and C. L. Stewart for providing reagents; and T. Barratt, J. Bao, D. Butkis, L. Evangelisti, C. Hughes and J. Musco for technical assistance. R.J.D. and R.A.F. are investigators, and D.D.Y. is an associate, of the Howard Hughes Medical Institute. This work was supported by the Howard Hughes Medical Institute (R.J.D. and R.A.F.) and Public Health Service grants (R.J.D. and P.R.).

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Author notes

  1. Derek D. Yang, Chia-Yi Kuan and Mercedes Rinócn: These authors contributed equally to this work

Authors and Affiliations

  1. Section of Immunobiology, New Haven, 06510, Connecticutt, USA

    Derek D. Yang, Mercedes Rinócn, Timothy S. Zheng & Richard A. Flavell

  2. Howard Hughes Medical Institute, New Haven, 06510, Connecticutt, USA

    Derek D. Yang, Alan J. Whitmarsh, Roger J. Davis & Richard A. Flavell

  3. Section of Neurobiology, Yale University School of Medicine, New Haven, 06510, Connecticutt, USA

    Chia-Yi Kuan & Pasko Rakic

  4. Department of Biochemistry and Molecular Biology, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, 01605, Massachusetts, USA

    Alan J. Whitmarsh & Roger J. Davis

  5. Department of Medicine, Immunobiology Program, University of Vermont, Burlington, 05405, Vermont, USA

    Mercedes Rinócn

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Correspondence to Richard A. Flavell.

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Yang, D., Kuan, CY., Whitmarsh, A. et al. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 389, 865–870 (1997). https://doi.org/10.1038/39899

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