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Shared receptors in axon guidance: SAX-3/Robo signals via UNC-34/Enabled and a Netrin-independent UNC-40/DCC function

Abstract

The C. elegans SAX-3/Robo receptor acts in anterior–posterior, dorsal–ventral and midline guidance decisions. Here we show that SAX-3 signaling involves the C. elegans Enabled protein UNC-34 and an unexpected Netrin-independent function of the Netrin receptor UNC-40/DCC. Genetic interactions with gain- and loss-of-function mutations suggest that unc-34 and unc-40 act together with sax-3 in several guidance decisions, but the C. elegans Netrin gene unc-6 does not act in the same genetic pathways. Within the migrating axon, sax-3, unc-34 and unc-40 all act cell-autonomously. Our results support a role for UNC-34/Enabled proteins in SAX-3-mediated repulsion, and show that UNC-40/DCC can potentiate SAX-3/Robo signaling via a mechanism that may involve direct binding of the two guidance receptors. A combinatorial logic dictates alternative functions for UNC-40/DCC, which can act in attraction to UNC-6/Netrin, repulsion from Netrin (with UNC-5), or repulsion from Slit (with SAX-3).

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Figure 1: unc-34 and sax-3 mutants share axon guidance phenotypes at the ventral midline and in ventral guidance.
Figure 2: unc-34 double mutant analysis in AVM ventral guidance.
Figure 3: Suppression of Slit gain-of-function phenotypes by unc-34 and unc-40.
Figure 4: Genetic interactions between sax-3 and unc-34 in the nerve ring.
Figure 5: Genetic interactions between sax-3 and unc-40 in the nerve ring.
Figure 6: SAX-3, UNC-34 and UNC-40 proteins can associate in vitro.

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Acknowledgements

We thank K. Prehoda, D. Lee, J. Zallen, S. Clark and Z. Gitai for discussions and ideas that facilitated this work, M. Dell and G. Garriga for communicating results before publication, S. Clark, P. Sengupta, A. Fire and J. Culotti for clones and strains, and C. Adler, T. Saxton, S. Shaham and E. Stein for comments on the manuscript. T.W.Y. was supported by a MIND Institute predoctoral fellowship and the UCSF MSTP. J.C.H. was supported by an HHMI predoctoral fellowship. C.I.B. and M.T.L. are Investigators of the Howard Hughes Medical Institute. This work was supported by the Howard Hughes Medical Institute.

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Correspondence to Cornelia I. Bargmann.

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Yu, T., Hao, J., Lim, W. et al. Shared receptors in axon guidance: SAX-3/Robo signals via UNC-34/Enabled and a Netrin-independent UNC-40/DCC function. Nat Neurosci 5, 1147–1154 (2002). https://doi.org/10.1038/nn956

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