Comprehensive analyses of the axon guidance molecule Draxin

神经系统的功能取决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性和排斥性引导线索的组合效应引导轴突向其中间目标生长，从而在形成神经元之间的适当连接方面发挥关键作用。轴突导向因子的四个保守家族，netrin，semaphorin，ephrin和slit蛋白，分别通过DCC或UNC 5，Neuropilin/Plexin，Eph和Robo家族的受体介导其导向作用。虽然已经发现这些蛋白质调节各种各样的指导决定，但预计其他蛋白质正在等待鉴定，并将有助于解决神经系统的巨大复杂性。我们最近报道了一种新的轴突导向分子draxin的发现，其与其他已知的导向分子没有序列同源性（Islam等人，Science 2009）。在体外，Draxin可以排斥脊髓连合轴突的生长受到netrin-1的刺激;在体内，基因缺失的Draxin导致脊髓连合轴突的轻度引导缺陷，并在所有前脑连合的戏剧性损失，通过失去他们的生长方向线索，但不是通过他们的细胞death.Identification的Draxin受体是重要的，阐明其功能的精确机制。我们意外地发现netrin受体DCC以高亲和力结合Draxin，并且是Draxin对皮质神经突生长的抑制作用所需的。本研究确定DCC为Draxin的功能性受体或受体组分。接下来，我们需要确定哪些类型的信号分子被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.