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Neurotrophins use the Erk5 pathway to mediate a retrograde survival response

Nature Neuroscience volume 4, pages 981–988 (2001)Cite this article

A Corrigendum to this article was published on 01 October 2002

Abstract

Growth factors synthesized and released by target tissues promote survival and differentiation of innervating neurons. This retrograde signal begins when growth factors bind receptors at nerve terminals. Activated receptors are then endocytosed and transported through the axon to the cell body. Here we show that the mitogen-activated protein kinase (MAPK) signaling pathways used by neurotrophins during retrograde signaling differ from those used following direct stimulation of the cell soma. During retrograde signaling, endocytosed neurotrophin receptors (Trks) activate the extracellular signal-related protein kinase 5 (Erk5) pathway, leading to nuclear translocation of Erk5, phosphorylation of CREB, and enhanced neuronal survival. In contrast, Erk1/2, which mediates nuclear responses following direct cell body stimulation, does not transmit a retrograde signal. Thus, the Erk5 pathway has a unique function in retrograde signaling. Differential activation of distinct MAPK pathways may enable an individual growth factor to relay information that specifies the location and the nature of stimulation.

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Figure 1: Mek1/2 and Erk1/2 do not mediate the neurotrophin-induced retrograde signal.
Figure 2: Neurotrophin stimulation induces Erk5 activation and nuclear translocation.
Figure 3: Erk5 is activated during retrograde signaling.
Figure 4: Endocytosed Trks mediate retrograde signaling to Erk5 and CREB.
Figure 5: Activation of Erk5 promotes survival.

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Acknowledgements

We thank S. Gutkind (NIH) for Erk5 and Mek5 plasmids. We thank A. Welcher (Amgen, California) for donating the BDNF, T. Roberts for Raf1 antibodies and P. Silver for GFP antibodies (Dana-Farber, Massachusetts), M. Greenberg (Children's Hospital, Massachusetts) for P-CREB antibodies and E. Schaefer (QCB Biosource, Massachusetts) for P-Erk5 antibodies. We thank D. Moheban, M. Pazyra and D. Micomonaco for technical assistance. We thank M. Greenberg, J. Kornhauser, L. Parada and C. Stiles for comments. This work was supported by grants from NIH(NS35148) and the Klingenstein Foundation.

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Authors and Affiliations

  1. Department of Neurobiology, Harvard Medical School and Department of Pediatric Oncology, Dana 620, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Fiona L. Watson, Heather M. Heerssen & Rosalind A. Segal

  2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Anita Bhattacharyya

  3. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Laura Klesse

  4. Division of Neuroscience, Children's Hospital, Boston, 02115, Massachusetts, USA

    Michael Z. Lin

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  1. Fiona L. Watson
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Correspondence to Rosalind A. Segal.

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Watson, F., Heerssen, H., Bhattacharyya, A. et al. Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nat Neurosci 4, 981–988 (2001). https://doi.org/10.1038/nn720

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