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Metallothionein promotes regenerative axonal sprouting of dorsal root ganglion neurons after physical axotomy

Cellular and Molecular Life Sciences volume 69, pages 809–817 (2012)Cite this article

Abstract

Prior studies have reported that metallothionein I/II (MT) promote regenerative axonal sprouting and neurite elongation of a variety of central nervous system neurons after injury. In this study, we evaluated whether MT is capable of modulating regenerative axon outgrowth of neurons from the peripheral nervous system. The effect of MT was firstly investigated in dorsal root ganglion (DRG) explants, where axons were scratch-injured in the presence or absence of exogenous MT. The application of MT led to a significant increase in regenerative sprouting of neurons 16 h after injury. We show that the pro-regenerative effect of MT involves an interaction with the low-density lipoprotein receptor megalin, which could be blocked using the competitive antagonist RAP. Pre-treatment with the mitogen-activated protein kinase (MAPK) inhibitor PD98059 also completely abrogated the effect of exogenous MT in promoting axonal outgrowth. Interestingly, we only observed megalin expression in neuronal soma and not axons in the DRG explants. To investigate this matter, an in vitro injury model was established using Campenot chambers, which allowed the application of MT selectively into either the axonal or cell body compartments after scratch injury was performed to axons. At 16 h after injury, regenerating axons were significantly longer only when exogenous MT was applied solely to the soma compartment, in accordance with the localized expression of megalin in neuronal cell bodies. This study provides a clear indication that MT promotes axonal regeneration of DRG neurons, via a megalin- and MAPK-dependent mechanism.

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Acknowledgments

This research was supported by research grants from the Australian Research Council (DP0984673), the National Health and Medical Research Council of Australia (ID#544913), and the Motor Accident and Insurance Board of Tasmania. JYKL also received a travel fellowship from the Australian Academy of Sciences to visit the NIH (USA) to undertake some of the experiments reported in this study.

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Affiliations

  1. Menzies Research Institute, University of Tasmania, Private Bag 24, Hobart, TAS, 7001, Australia

    Jacqueline Y. K. Leung, William R. Bennett, Rosalind P. Herbert, Adrian K. West, Meng Inn Chuah & Roger S. Chung

  2. National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, 20892, USA

    Philip R. Lee, Hiroaki Wake & R. Douglas Fields

Authors
  1. Jacqueline Y. K. Leung
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  2. William R. Bennett
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  3. Rosalind P. Herbert
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  4. Adrian K. West
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  5. Philip R. Lee
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  6. Hiroaki Wake
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  7. R. Douglas Fields
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  8. Meng Inn Chuah
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  9. Roger S. Chung
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Correspondence to Roger S. Chung.

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Leung, J.Y.K., Bennett, W.R., Herbert, R.P. et al. Metallothionein promotes regenerative axonal sprouting of dorsal root ganglion neurons after physical axotomy. Cell. Mol. Life Sci. 69, 809–817 (2012). https://doi.org/10.1007/s00018-011-0790-7

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  • DOI: https://doi.org/10.1007/s00018-011-0790-7

Keywords

  • Metallothionein
  • Neuronal injury
  • Neurite sprouting
  • Megalin
  • Dorsal root ganglion neurons