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Netrin signal transduction and the guanine nucleotide exchange factor DOCK180 in attractive signaling

Nature Neuroscience volume 11, pages 28–35 (2008)Cite this article

Abstract

Netrins are prototypical axon guidance cues whose attractive signaling requires the small GTPase Rac1. It remains unclear how Rac1 is regulated in the netrin pathway. DOCK180 is a member of a new family of guanine nucleotide exchange factors for Rho GTPases. Here we provide evidence implicating DOCK180 in netrin signal transduction. Netrin promoted the formation of a protein-protein interaction complex that included DOCK180 and the netrin receptor deleted in colorectal carcinoma (DCC). Inhibition of DOCK180 reduced activation of Rac1 by netrin. Both axon outgrowth and axon attraction induced by netrin were inhibited after DOCK180 knockdown in vertebrate neurons. The in vivo functional role of DOCK180 was demonstrated by its requirement for projection of commissural axons in the neural tube. These findings indicate that netrin stimulation recruits DOCK180 through DCC, which then activates small GTPases, suggesting an essential role for DOCK180 in mediating attractive responses by neurons to netrin-1.

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Figure 1: Subcellular localization of DOCK180, DCC and Rac1 in the growth cones of primary neurons.
Figure 2: Interaction between DOCK180 and DCC.
Figure 3: Involvement of DOCK180 in Rac1 activation by netrin-1.
Figure 4: DOCK180 shRNA inhibited axon outgrowth induced by netrin.
Figure 5: Inhibition of netrin-1–induced turning of commissural axons by DOCK180-ISP and DOCK180 siRNA.
Figure 6: DOCK180 siRNA caused in vivo misguidance of commissural axons.

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Acknowledgements

We are grateful to K.S. Ravichandran and K. Vuori for DOCK180 constructs, to E.T. Stoeckli for the antibody to axonin-1, to E. Kiyokawa for an antibody to DOCK180, to R.J. Miller and P.T. Toth for help with confocal imaging, and to the US National Institutes of Health for support (to Y.R., J.W. and W.X.).

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  1. Xiaoling Li, Xue Gao and Guofa Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Northwestern University Feinberg School of Medicine, 303 E. Superior Avenue, Chicago, 60611, Illinois, USA

    Xiaoling Li, Xue Gao, Guofa Liu, Jane Wu & Yi Rao

  2. Department of Neurology, Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, 1120 15th Street, CA 4010, Medical College of Georgia, Augusta, 30912, Georgia, USA

    Wencheng Xiong

  3. Robert H. Lurie Comprehensive Cancer Center and the Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, 303 E. Superior Avenue, Lurie 6–117, Chicago, 60611, Illinois, USA

    Jane Wu

  4. School of Life Sciences, Beijing University, 100871, Beijing, China

    Yi Rao

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Correspondence to Jane Wu or Yi Rao.

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Li, X., Gao, X., Liu, G. et al. Netrin signal transduction and the guanine nucleotide exchange factor DOCK180 in attractive signaling. Nat Neurosci 11, 28–35 (2008). https://doi.org/10.1038/nn2022

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