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Identification of a lectin causing the degeneration of neuronal processes using engineered embryonic stem cells

Nature Neuroscience volume 10, pages 712–719 (2007)Cite this article

Abstract

Unlike the mechanisms involved in the death of neuronal cell bodies, those causing the elimination of processes are not well understood owing to the lack of suitable experimental systems. As the neurotrophin receptor p75NTR is known to restrict the growth of neuronal processes, we engineered mouse embryonic stem (ES) cells to express an Ngfr (p75NTR) cDNA under the control of the Mapt locus (the gene encoding tau), which begins to be active when ES cell–derived progenitors start elongating processes. This caused a progressive, synchronous degeneration of all processes, and a prospective proteomic analysis showed increased levels of the sugar-binding protein galectin-1 in the p75NTR-engineered cells. Function-blocking galectin-1 antibodies prevented the degeneration of processes, and recombinant galectin-1 caused the processes of wild-type neurons to degenerate first, followed by the cell bodies. In vivo, the application of a glutamate receptor agonist, a maneuver known to upregulate p75NTR, led to an increase in the amount of galectin-1 and to the degeneration of neurons and their processes in a galectin-1–dependent fashion. Section of the sciatic nerve also rapidly upregulated levels of p75NTR and galectin-1 in terminal Schwann cells, and the elimination of nerve endings was delayed at the neuromuscular junction of mice lacking Lgals1 (the gene encoding galectin-1). These results indicate that galectin-1 actively participates in the elimination of neuronal processes after lesion, and that engineered ES cells are a useful tool for studying relevant aspects of neuronal degeneration that have been hitherto difficult to analyze.

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Figure 1: Expression of Ngfr causes the degeneration of neuronal processes before the death of cell bodies.
Figure 2: Identification of galectin-1 in Mapt::Ngfr neurons.
Figure 3: Galectin-1 causes the degeneration of neuronal process.
Figure 4: p75NTR controls galectin-1 levels.
Figure 5: Galectin-1 mediates the degeneration of neurons caused by excitotoxicity.
Figure 6: Delayed elimination of nerve endings in Lgals-null mice.

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Acknowledgements

We thank G. Dechant and A. Le Bivic for discussions, P. Barker for gifts of reagents, R. Kuhn, J. Van Oostrum and J. Voshol (Novartis) for making our collaboration possible, P.-Y. Mantel for help with the generation of ES cell lines and T. Matsumoto, V. Nikoletopoulou and V. Bischoff for comments on the experiments. This study was supported by the Swiss National Foundation.

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Authors and Affiliations

  1. Biozentrum, University of Basel, Klingelbergstrasse 50/70, Basel, CH-4056, Switzerland

    Nicolas Plachta, Christine Annaheim, Shuo Lin, Markus Rüegg & Yves-Alain Barde

  2. Neuroscience Department, Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland

    Stephanie Bissière & Miriam Bibel

  3. Genome and Proteome Sciences Department, Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland

    Sjouke Hoving & Dieter Müller

  4. Institut Jacques Monod, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7592, P6 and P7 Universities, Paris Cedex, France

    Françoise Poirier

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  1. Nicolas Plachta
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Contributions

M.B. developed the ES cell–based differentiation system and generated the Mapt::Ngfr cells, and C.A. generated the Ngfr−/− ES cells. S.H. and D.M. carried out the proteomic analysis. S.B. carried out the in vivo rat experiments, and S.L. and M.R. analyzed the axotomy experiments. F.P. generated the Lgals1 mutant mice. N.P. and Y.-A.B. designed and carried out all other experiments.

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Correspondence to Yves-Alain Barde.

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Plachta, N., Annaheim, C., Bissière, S. et al. Identification of a lectin causing the degeneration of neuronal processes using engineered embryonic stem cells. Nat Neurosci 10, 712–719 (2007). https://doi.org/10.1038/nn1897

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