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C. elegans VAB-8 and UNC-73 regulate the SAX-3 receptor to direct cell and growth-cone migrations

Nature Neuroscience volume 10, pages 169–176 (2007)Cite this article

Abstract

During nervous system development, a small number of conserved guidance cues and receptors regulate many axon trajectories. How could a limited number of cues and receptors regulate such complex projection patterns? One way is to modulate receptor function. Here we show that the Caenorhabditis elegans kinesin-related protein VAB-8L, which is necessary and sufficient for posterior cell and growth-cone migrations, directs these migrations by regulating the levels of the guidance receptor SAX-3 (also known as robo). Genetic experiments indicate that VAB-8L and the Rac guanine nucleotide exchange factor activity of UNC-73 (trio) increase the ability of the SLT-1 (slit) and UNC-6 (netrin) guidance pathways to promote posterior guidance. The observations of higher SAX-3 receptor abundance in animals with increasing amounts of VAB-8L, and of physical interactions between UNC-73 and both VAB-8L and the intracellular domain of the SAX-3, support a model whereby VAB-8L directs cell and growth-cone migrations by promoting localization of guidance receptors to the cell surface.

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Figure 1: VAB-8L expression in the ALM neurons reroutes their processes posteriorly.
Figure 2: Mutations in genes encoding UNC-73, guidance cues and their receptors suppress VAB-8L–dependent ALM rerouting.
Figure 3: Posterior rerouting of ALM caused by excess SAX-3.
Figure 4: Loss or reduction of VAB-8, UNC-73, SAX-3, UNC-5 and UNC-6 perturb ALM cell migration.
Figure 5: VAB-8L level affects the SAX-3::GFP level in ALMs and BDUs of early embryos.
Figure 6: Interactions of UNC-73B with VAB-8L, SAX-3, UNC-5 and UNC-40 in the yeast two-hybrid analysis.

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Acknowledgements

We thank N. Levy-Strumpf and J. Culotti for critical discussions, sharing of unpublished results and comments on the manuscript. This work was made possible by their observations on vab-8 and unc-40 interactions, and we are greatly indebted to them for sharing this information. We also thank C. Bargmann and R. Steven for helpful discussions and reagents; T. Lai for the Pmec-3::gfp and Pmec-7::gfp constructs; and the C. elegans Genetics Center for some of the strains used in this study; Y. Kohara for C. elegans EST clones; and P. Vanderzalm for comments on the manuscript. We are grateful to members of Garriga and Goshima labs for helpful suggestions. This work was supported by Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Grants-in-Aid for Scientific Research in a Priority Area from the Ministry of Education, Sports and Culture to K.O. and Y.G., by the Yokohama Foundation for Advancement of Medical Science to K.O., and by the US National Institutes of Health grant NS32057 to G.G.

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Author notes

  1. Fred W Wolf

    Present address: Ernest Gallo Clinic & Research Center, 5858 Horton St., Suite 200, Emeryville, California, 94608, USA

Authors and Affiliations

  1. Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, 94720-3204, California, USA

    Natsuko Watari-Goshima, Fred W Wolf & Gian Garriga

  2. Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan

    Ken-ichi Ogura & Yoshio Goshima

  3. CREST Japan Science and Technology Corporation, Kawaguchi, 332-0012, Japan

    Yoshio Goshima

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Correspondence to Gian Garriga.

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Supplementary information

Supplementary Fig. 1

Sax-3 functions in the ALM to promote ALM rerouting. (PDF 544 kb)

Supplementary Fig. 2

Physical interaction with UNC-73 in yeast two-hybrid analysis. (PDF 2539 kb)

Supplementary Fig. 3

Model for VAB-8L-dependent effects on ALM cell migration and process rerouting. (PDF 1366 kb)

Supplementary Table 1

VAB-8L-dependent ALM process rerouting. (PDF 56 kb)

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Watari-Goshima, N., Ogura, Ki., Wolf, F. et al. C. elegans VAB-8 and UNC-73 regulate the SAX-3 receptor to direct cell and growth-cone migrations. Nat Neurosci 10, 169–176 (2007). https://doi.org/10.1038/nn1834

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