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Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos

Nature Neuroscience volume 7, pages 1250–1258 (2004)Cite this article

Abstract

Neuregulin-1 (Nrg-1) contains an intracellular domain (Nrg-ICD) that translocates into the nucleus, where it may regulate gene expression upon neuronal depolarization. However, the identity of its target promoters and the mechanisms by which it regulates transcription have been elusive. Here we report that, in the mouse cochlea, synaptic activity increases the level of nuclear Nrg-ICD and upregulates postsynaptic density protein-95 (PSD-95), a scaffolding protein that is enriched in post-synaptic structures. Nrg-ICD enhances the transcriptional activity of the PSD-95 promoter by binding to a zinc-finger transcription factor, Eos. The Nrg-ICD–Eos complex induces endogenous PSD-95 expression in vivo through a signaling pathway that is mostly independent of γ-secretase regulation. This upregulation of PSD-95 expression by the Nrg-ICD–Eos complex provides a molecular basis for activity-dependent synaptic plasticity.

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Figure 1: Upregulation of PSD-95 and nuclear Nrg-ICD after synaptic activation.
Figure 2: Activation of PSD-95 promoter by the Nrg-ICD and Eos complex on Ikaros sites.
Figure 3: Nrg-ICD-Eos nuclear signaling is mainly independent of γ-secretase.
Figure 4: Regulation of endogenous PSD-95 by Nrg-1 and Eos.
Figure 5: Synaptic activity–dependent activation of PSD-95 promoter by Nrg-ICD.

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Acknowledgements

We thank J. Sanes for insightful suggestions and critical reading of the manuscript, A.M. Craig and E. Johnson for critical reading of the manuscript, B. Strooper for providing the PS1− PS2− cell line, D. Stathakis for providing PSD-95 promoters and M. Crossley for mammalian expression vectors for Eos and Pegasus. Special thanks to Y. Yu for assisting in the experiments. Supported by grants AG01016 (J.B.) and AG05681 (J.B.) from the US National Institute on Aging.

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Authors and Affiliations

  1. Department of Otolaryngology, Washington University, St. Louis, 63110, Missouri, USA

    Jianxin Bao, Debin Lei, Abdullah Osman & Kevin K Ohlemiller

  2. Center for Aging, Washington University, St. Louis, 63110, Missouri, USA

    Jianxin Bao, Debin Lei & Abdullah Osman

  3. Department of Neurology, Washington University, St. Louis, 63110, Missouri, USA

    Yannan Ouyang

  4. Department of Anatomy and Cell Biology, Columbia University, New York, 10032, New York, USA

    Hana Lin & Richard T Ambron

  5. Department of Pathology, Columbia University, New York, 10032, New York, USA

    Tae-Wan Kim

  6. Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, 30912, Georgia, USA

    Lin Mei & Penggao Dai

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Supplementary information

Supplementary Table 1

Up-regulated genes after neuronal activity. (DOC 26 kb)

Supplementary Table 2

Down-regulated genes after neuronal activity. (DOC 34 kb)

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Bao, J., Lin, H., Ouyang, Y. et al. Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos. Nat Neurosci 7, 1250–1258 (2004). https://doi.org/10.1038/nn1342

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