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The Drosophila Netrin receptor Frazzled guides axons by controlling Netrin distribution

Nature volume 406, pages 886–889 (2000)Cite this article

Abstract

Netrin is a secreted protein that can act as a chemotropic axon guidance cue1,2. Two classes of Netrin receptor, DCC3,4,5 and UNC-5 (refs 6,7,8,9), are required for axon guidance3,4,6,7,8,9,10,11 and are thought to mediate Netrin signals in growth cones through their cytoplasmic domains12,13. However, in the guidance of Drosophila photoreceptor axons, the DCC orthologue Frazzled3 is required not in the photoreceptor neurons but instead in their targets, indicating that Frazzled also has a non-cell-autonomous function14. Here we show that Frazzled can capture Netrin and ‘present’ it for recognition by other receptors. Moreover, Frazzled itself is actively localized within the axon through its cytoplasmic domain, and thereby rearranges Netrin protein into a spatial pattern completely different from the pattern of Netrin gene expression. Frazzled-dependent guidance of one pioneer neuron in the central nervous system can be accounted for solely on the basis of this ability of Frazzled to control Netrin distribution, and not by Frazzled signalling. We propose a model of patterning mechanism in which a receptor rearranges secreted ligand molecules, thereby creating positional information for other receptors.

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Figure 1: Frazzled relocates Netrin.
Figure 2: Functional domains of the Frazzled molecule.
Figure 3: Axonal guidance of dMP2.
Figure 4: MP2 growth cones respond to ectopic Netrin-B.The behaviour of the dMP2 growth cones in wild type (a) and upon ectopic expression of Fra-ΔC (b; UAS–fra-ΔC/G4-605) and Netrin-B (c; UAS–Netrin-B/G4-605). dMP2 growth cones (red) visualized by monoclonal antibody 22C10 in stage 12/0 embryos.

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Acknowledgements

We thank A. Chiba, C. S. Goodman, A. Hidalgo, P. Kolodziej, M. Seeger and G. Technau for fly strains; P. Kolodziej and M. Seeger for DNA clones and antibodies; T. Hosoya, Y. Umesono, M. Okabe and all members of the Hotta laboratory for helpful discussions; and Y. Fujioka, M. Seki, M. Sakai and C. Asaka for technical assistance. This work was funded by CREST (Y. Hotta and Y. Hiromi), the Ministry of Education, Science, Sports, and Culture of Japan, and Research for the Future Program of JSPS (Y. Hiromi) and NIH (E.G.).

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Authors and Affiliations

  1. Department of Developmental Genetics National Institute of Genetics,

    Masaki Hiramoto, Yasushi Hiromi & Yoshiki Hotta

  2. Department of Genetics, Graduate University for Advanced Studies, 1111 Yata, Mishima, 411-8540, Shizuoka, Japan

    Yasushi Hiromi & Yoshiki Hotta

  3. Fred Hutchinson Cancer Research Center, North, 1100 Fairview Ave, Seattle, 98109, Washington, USA

    Edward Giniger

  4. CREST fellow,

    Masaki Hiramoto

  5. CREST Researcher of Japan Science and Technology Corporation, 4-1-8, Honcho, Kawaguchi , 332-0012, Japan

    Yoshiki Hotta

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  1. Masaki Hiramoto
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Correspondence to Yoshiki Hotta.

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Hiramoto, M., Hiromi, Y., Giniger, E. et al. The Drosophila Netrin receptor Frazzled guides axons by controlling Netrin distribution. Nature 406, 886–889 (2000). https://doi.org/10.1038/35022571

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