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Nat Neurosci. 2002 Nov;5(11):1147-54.

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

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Howard Hughes Medical Institute, Program in Neuroscience, Department of Anatomy and of Biochemistry and Biophysics, The University of California, San Francisco, California 94143, USA.


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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