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EGF transactivation of Trk receptors regulates the migration of newborn cortical neurons

Nature Neuroscience volume 16, pages 407–415 (2013)Cite this article

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Abstract

The development of neuronal networks in the neocortex depends on control mechanisms for mitosis and migration that allow newborn neurons to find their accurate position. Multiple mitogens, neurotrophic factors, guidance molecules and their corresponding receptors are involved in this process, but the mechanisms by which these signals are integrated are only poorly understood. We found that TrkB and TrkC, the receptors for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are activated by epidermal growth factor receptor (EGFR) signaling rather than by BDNF or NT-3 in embryonic mouse cortical precursor cells. This transactivation event regulated migration of early neuronal cells to their final position in the developing cortex. Transactivation by EGF led to membrane translocation of TrkB, promoting its signaling responsiveness. Our results provide genetic evidence that TrkB and TrkC activation in early cortical neurons do not depend on BDNF and NT-3, but instead on transactivation by EGFR signaling.

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Figure 1: Expression and activation of TrkB by EGF in cortical precursors.
Figure 2: EGF is the major activator of TrkB in cortical precursor cells.
Figure 3: Characterization of TrkB transactivation by EGFR signaling.
Figure 4: Characterization of the 170-kDa band recognized by the pTrk-PLCγ antibody.
Figure 5: Translocation of TrkB to the cell surface of cortical precursor cells in response to EGF.
Figure 6: Reduced transactivation of TrkB in Egfr−/− mice affects the formation of the cortical plate.

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Acknowledgements

We would like to thank M. Sibilia (Medical University of Vienna) for providing Egfr−/− mice, Y.A. Barde (University of Basel ) for the HA-TrkB construct, K. Walter for excellent technical assistance, and W. Fouquet and S. Sigrist for their help in STED microscopy. This work was supported by the Deutsche Forschungsgemeinschaft, grants SFB 487, C4 (N.O.) and SFB 581, B4 (D.P. and M.S.), ForNeuroCell (M.S.) and by US National Institutes of Health grant NS21072-24 (M.V.C.).

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Authors and Affiliations

  1. Institute for Clinical Neurobiology, University of Wuerzburg, Wuerzburg, Germany

    Dirk Puehringer, Nadiya Orel, Patrick Lüningschrör, Narayan Subramanian, Thomas Herrmann & Michael Sendtner

  2. Molecular Neurobiology Program, Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA

    Moses V Chao

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Contributions

D.P. and M.S. designed the experiments. M.V.C. and T.H. provided tools and were involved in the early design of this study. D.P. performed most of the experiments. N.S. helped with the initial design and generation of lentiviruses for TrkB knockdown. T.H. generated viruses for dominant-negative Src. P.L. helped with biotin streptavidin cell surface protein isolation. N.O. helped with cell culture techniques for neural stem cells and performed the experiments. D.P. and M.S. wrote the manuscript.

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Correspondence to Michael Sendtner.

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Puehringer, D., Orel, N., Lüningschrör, P. et al. EGF transactivation of Trk receptors regulates the migration of newborn cortical neurons. Nat Neurosci 16, 407–415 (2013). https://doi.org/10.1038/nn.3333

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