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UNC-129 regulates the balance between UNC-40 dependent and independent UNC-5 signaling pathways

Nature Neuroscience volume 12, pages 150–155 (2009)Cite this article

Abstract

The UNC-5 receptor mediates axon repulsion from UNC-6/netrin through UNC-40 dependent (UNC-5 + UNC-40) and independent (UNC-5 alone) signaling pathways. It has been shown that UNC-40–dependent signaling is required for long-range repulsion of UNC-6/netrin; however, the mechanisms used to regulate distinct UNC-5 signaling pathways are poorly understood. We found that the C. elegans transforming growth factor β (TGF-β) family ligand UNC-129, graded opposite to UNC-6/netrin, functions independent of the canonical TGF-β receptors to regulate UNC-5 cellular responses. Our observations indicates that UNC-129 facilitates long-range repulsive guidance of UNC-6 by enhancing UNC-5 + UNC-40 signaling at the expense of UNC-5 alone signaling through interaction with the UNC-5 receptor. This increases the set point sensitivity of growth cones to UNC-6/netrin as they simultaneously migrated up the UNC-129 gradient and down the UNC-6 gradient. Similar regulatory interactions between oppositely graded extracellular cues may be a common theme in guided cell and axon migrations.

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Figure 1: UNC-129 acts in the UNC-5 + UNC-40 pathway to regulate axon guidance and DTC migration.
Figure 2: UNC-129 acts in the UNC-5 + UNC-40 pathway to regulate DTC migration.
Figure 3: UNC-129 works in the UNC-5 + UNC-40 pathway to prevent male ray fusions.
Figure 4: Ectopic expression of UNC-129 interferes with UNC-5 alone signaling.
Figure 5: UNC-129 is an UNC-5–binding protein.

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Acknowledgements

We would like to thank K. Fujisawa, T. Kawano, R. Steven and C. LeRoy for helpful discussions, L. Brown for help with microscopy, M. Barrios-Rodiles for help with luciferase assays, and S. Suo and J. Plummer for careful reading of the manuscript. Funding for this work was provided by grants from the US National Institutes of Health (NS41397 to J.G.C.), the Canadian Institutes of Health Research (12860 to J.L.W. and GSP36651 to T.P.), the Canadian Institutes of Health Research Barbara Turnbull award (MOP77722 to J.G.C.) and the Cancer Research Society of Canada (L.T.M.). J.L.W. and J.G.C. are Canada Research Chairs. T.P. is a Distinguished Scientist of the Canadian Institutes of Health Research. J.L.W. is a Howard Hughes Medical Institute international scholar.

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Authors and Affiliations

  1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, M5G 1X5, Ontario, Canada.

    Lesley T MacNeil, W Rod Hardy, Tony Pawson, Jeffrey L Wrana & Joseph G Culotti

  2. Department of Molecular and Medical Genetics, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Lesley T MacNeil, W Rod Hardy, Tony Pawson, Jeffrey L Wrana & Joseph G Culotti

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  1. Lesley T MacNeil
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Contributions

W.R.H. made the UNC-5–HA and Gluc–UNC-129 constructs. L.T.M. and W.R.H. caried out the luciferase assays. All other experiments were performed by L.T.M. J.L.W. and J.G.C. supervised the project. T.P. provided reagents. L.T.M., J.L.W. and J.G.C. wrote the manuscript.

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Correspondence to Joseph G Culotti.

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MacNeil, L., Hardy, W., Pawson, T. et al. UNC-129 regulates the balance between UNC-40 dependent and independent UNC-5 signaling pathways. Nat Neurosci 12, 150–155 (2009). https://doi.org/10.1038/nn.2256

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