Killeen Marie T, Sybingco Stephanie S
Department of Chemistry and Biology, Ryerson University, 350 Victoria Street, Toronto, Ontario, Canada M5B 2K3.
Dev Biol. 2008 Nov 15;323(2):143-51. doi: 10.1016/j.ydbio.2008.08.027. Epub 2008 Sep 5.
One of the challenges to understanding nervous system development has been to establish how a fairly limited number of axon guidance cues can set up the patterning of very complex nervous systems. Studies on organisms with relatively simple nervous systems such as Drosophila melanogaster and C. elegans have provided many insights into axon guidance mechanisms. The axons of many neurons migrate along both the dorsal-ventral (DV) and the anterior-posterior (AP) axes at different phases of development, and in addition they may also cross the midline. Axon migration in the dorsal-ventral (DV) direction is mainly controlled by Netrins with their receptors; UNC-40/DCC and UNC-5, and the Slits with their receptors; Robo/SAX-3. Axon guidance in the anterior-posterior (AP) axis is mainly controlled by Wnts with their receptors; the Frizzleds/Fz. An individual axon may be subjected to opposing attractive and repulsive forces coming from opposite sides in the same axis but there may also be opposing cues in the other axis of migration. All the information from the cues has to be integrated within the growth cone at the leading edge of the migrating axon to elicit a response. Recent studies have provided insight into how this is achieved. Evidence suggests that the axis of axon migration is determined by the manner in which Netrin, Slit and Wnt receptors are polarized (localized) within the neuron prior to axon outgrowth. The same molecules are involved in both axon outgrowth and axon guidance, for at least some neurons in C. elegans, whether the cue is the attractive cue UNC-6/Netrin working though UNC-40/DCC or the repulsive cue SLT-1/Slit working though the receptor SAX-3/Robo (Adler et al., 2006, Chang et al., 2006, Quinn et al., 2006, 2008). The molecules involved in cell signaling in this case are polarized within the cell body of the neuron before process outgrowth and direct the axon outgrowth. Expression of the Netrin receptor UNC-40/DCC or the Slit receptor SAX-3/Robo in axons that normally migrate in the AP direction causes neuronal polarity reversal in a Netrin and Slit independent manner (Levy-Strumpf and Culotti 2007, Watari-Goshima et al., 2007). Localization of the receptors in this case is caused by the kinesin-related VAB-8L which appears to govern the site of axon outgrowth in these neurons by causing receptor localization. Therefore, asymmetric localization of axon guidance receptors is followed by axon outgrowth in vivo using the receptor's normal cue, either attractive, repulsive or unknown cues.
理解神经系统发育面临的挑战之一是确定数量相对有限的轴突导向线索如何构建非常复杂的神经系统模式。对具有相对简单神经系统的生物体（例如果蝇和秀丽隐杆线虫）的研究为轴突导向机制提供了许多见解。许多神经元的轴突在发育的不同阶段沿背腹（DV）轴和前后（AP）轴迁移，此外它们还可能穿过中线。轴突在背腹（DV）方向的迁移主要由Netrins及其受体UNC - 40/DCC和UNC - 5，以及Slits及其受体Robo/SAX - 3控制。轴突在前后（AP）轴的导向主要由Wnts及其受体Frizzleds/Fz控制。单个轴突可能受到来自同一轴相反两侧的相反吸引和排斥力的作用，但在另一个迁移轴上也可能存在相反的线索。来自这些线索的所有信息都必须在迁移轴突前缘的生长锥内整合以引发反应。最近的研究揭示了这是如何实现的。有证据表明，轴突迁移的轴是由Netrin、Slit和Wnt受体在轴突生长之前在神经元内极化（定位）的方式决定的。对于秀丽隐杆线虫中的至少一些神经元，轴突生长和轴突导向涉及相同的分子，无论线索是通过UNC - 40/DCC起作用的吸引性线索UNC - 6/Netrin还是通过受体SAX - 3/Robo起作用的排斥性线索SLT - 1/Slit（Adler等人，2006年，Chang等人，2006年，Quinn等人，2006年，2008年）。在这种情况下，参与细胞信号传导的分子在轴突生长之前在神经元的细胞体内极化，并指导轴突生长。在通常沿AP方向迁移的轴突中表达Netrin受体UNC - 40/DCC或Slit受体SAX - 3/Robo会以与Netrin和Slit无关的方式导致神经元极性反转（Levy - Strumpf和Culotti，2007年，Watari - Goshima等人，2007年）。在这种情况下，受体的定位是由与驱动蛋白相关的VAB - 8L引起的，它似乎通过导致受体定位来控制这些神经元中轴突生长的位点。因此，轴突导向受体的不对称定位之后是体内轴突利用受体的正常线索生长，这些线索可以是吸引性的、排斥性的或未知的线索。
