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UNC-6/Netrin induces neuronal asymmetry and defines the site of axon formation

Nature Neuroscience volume 9, pages 511–518 (2006)Cite this article

Abstract

UNC-6/Netrin and its receptor UNC-40/DCC are conserved regulators of growth cone guidance. By directly observing developing neurons in vivo, we show that UNC-6 and UNC-40 also function during axon formation to initiate, maintain and orient asymmetric neuronal growth. The immature HSN neuron of Caenorhabditis elegans breaks spherical symmetry to extend a leading edge toward ventral UNC-6. In unc-6 and unc-40 mutants, leading edge formation fails, the cell remains symmetrical until late in development and the axon that eventually forms is misguided. Thus netrin has two activities: one that breaks neuronal symmetry and one that guides the future axon. As the axon forms, UNC-6, UNC-40 and the lipid modulators AGE-1/phosphoinositide 3-kinase (PI3K) and DAF-18/PTEN drive the actin-regulatory pleckstrin homology (PH) domain protein MIG-10/lamellipodin ventrally in HSN to promote asymmetric growth. The coupling of a directional netrin cue to sustained asymmetric growth via PI3K signaling is reminiscent of polarization in chemotaxing cells.

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Figure 1: Development of HSN in wild-type C. elegans.
Figure 2: HSN neurites are microtubule-containing, actin-rich structures.
Figure 3: HSN development in netrin mutants.
Figure 4: Heat-inducible expression of UNC-6/netrin induces leading edge formation in HSN.
Figure 5: UNC-40::GFP and MIG-10::YFP are ventrally localized in HSN.
Figure 6: MIG-10::YFP localizes ventrally in a netrin-dependent manner.

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Acknowledgements

We thank M. Krause, F. Gertler, M. Dell, G. Garriga and C. Chang for sharing results before publication; B. Wadsworth, Z. Gitai, T. Yu, G. Seydoux, M. Krause, F. Gertler and E. Lundquist for reagents used in this study; A. North at the Bio-Imaging Center at Rockefeller University; the Caenorhabditis Genetics Center for strains; K. Kemphues and R. Aroian for antibodies; and K. McDonald for use of the Bal-Tec HPM 010 high pressure freezing device and Leica AFS freeze-substitution device at the University of California Berkeley. We thank M. Hatten, M. Hilliard, S. Chalasani, M. Gallegos, G. Hollopeter, J. Gray and F. Kelly for thoughtful comments on the manuscript. This work was funded by a University of California San Francisco Chancellor's Fellowship to C.E.A. and by the Howard Hughes Medical Institute. C.I.B. is an Investigator of the Howard Hughes Medical Institute.

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  1. Howard Hughes Medical Institute, Laboratory of Neural Circuits and Behavior, Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Carolyn E Adler, Richard D Fetter & Cornelia I Bargmann

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Correspondence to Cornelia I Bargmann.

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Supplementary information

Supplementary Fig. 1

Effects of UNC-40 target genes on HSN development. (PDF 629 kb)

Supplementary Fig. 2

Dorsally localized MIG-10::YFP in an unc-129::unc-6 animal. (PDF 269 kb)

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Adler, C., Fetter, R. & Bargmann, C. UNC-6/Netrin induces neuronal asymmetry and defines the site of axon formation. Nat Neurosci 9, 511–518 (2006). https://doi.org/10.1038/nn1666

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