Research Article

Hierarchical Organization of Guidance Receptors: Silencing of Netrin Attraction by Slit Through a Robo/DCC Receptor Complex

Science  09 Mar 2001:
Vol. 291, Issue 5510, pp. 1928-1938
DOI: 10.1126/science.1058445

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Abstract

Axonal growth cones that cross the nervous system midline change their responsiveness to midline guidance cues: They become repelled by the repellent Slit and simultaneously lose responsiveness to the attractant netrin. These mutually reinforcing changes help to expel growth cones from the midline by making a once-attractive environment appear repulsive. Here, we provide evidence that these two changes are causally linked: In the growth cones of embryonic Xenopusspinal axons, activation of the Slit receptor Roundabout (Robo) silences the attractive effect of netrin-1, but not its growth-stimulatory effect, through direct binding of the cytoplasmic domain of Robo to that of the netrin receptor DCC. Biologically, this hierarchical silencing mechanism helps to prevent a tug-of-war between attractive and repulsive signals in the growth cone that might cause confusion. Molecularly, silencing is enabled by a modular and interlocking design of the cytoplasmic domains of these potentially antagonistic receptors that predetermines the outcome of their simultaneous activation.

  • * To whom correspondence should be addressed. E-mail: marctl{at}itsa.ucsf.edu

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