Comprehensive analyses of the axon guidance molecule Draxin

神经系统的功能依赖于精确而复杂的神经元连接的建立。细胞外环境中存在的吸引和排斥引导信号的组合效应，引导轴突向中间目标生长，因此在神经元之间形成适当的连接中起着至关重要的作用。四个保守的轴突引导信号家族，即netrin、semaphorin、ephrin和slit蛋白，分别通过DCC或UNC5、Neuropilin/Plexin、Eph和Robo家族的受体介导它们的引导作用。虽然已经发现这些蛋白质调节了各种各样的指导决策，但预计其他蛋白质还有待鉴定，并将有助于解决神经系统的巨大复杂性。我们最近报道发现了一种新的轴突引导分子，draxin，它与其他已知的引导分子没有序列同源性（Islam et al., Science 2009）。在体外，德拉辛可以排斥受netrin-1刺激生长的脊髓联合轴突；在体内，draxin基因缺失导致脊髓联合轴突的轻度引导缺陷，并通过失去其生长方向线索而导致所有前脑连接的显著丧失，但不会导致其细胞死亡。鉴别曲霉素受体对阐明其作用的确切机制具有重要意义。我们意外地发现，神经网络受体DCC与德拉辛具有高亲和力，并且是德拉辛抑制皮质神经突生长所必需的。本研究确定DCC是德拉辛的功能性受体或受体成分。接下来，我们需要确定哪些信号分子被draxin和DCC结合激活。

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.