Comprehensive analyses of the axon guidance molecule Draxin

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The function of the nervous system depends on the establishment of precise and intricate neuronal connections. The combinatorial effects of attractive and repulsive guidance cues, present in the extracellular environment, direct axons to grow towards their intermediate targets and thus play a crucial role in forming proper connections between neurons. Four conserved families of axon guidance cues, the netrin, semaphorin, ephrin and slit proteins, mediate their guidance effects via receptors of the DCC or UNC5, Neuropilin/Plexin, Eph and Robo families, respectively. Although these proteins have been found to regulate a wide variety of guidance decisions, it is expected that others await identification, and will help address the immense complexity of the nervous system. We recently reported the discovery of a novel axon guidance molecule, draxin, which shares no sequence homology with other known guidance molecules (Islam et al., Science 2009). In vitro, draxin can repel spinal commissural axons whose outgrowth is stimulated by netrin-1 ; in vivo, genetic deletion of draxin results in mild guidance defects of spinal commissural axons, and in a dramatic loss of all forebrain commissures by loosing their growing directional cues, but not by their cell death.Identification of the draxin receptor is important to elucidating the precise mechanism through which it functions. We found unexpectedly that the netrin-receptor DCC binds draxin with high affinity and is required for draxin's inhibitory effect on the cortical neurite outgrowth. This study identifies DCC as a functional receptor or receptor component for draxin. Next, we need to identify what kinds of signaling molecules are activated by draxin and DCC binding.