SYD-1C, UNC-40 (DCC) and SAX-3 (Robo) function interdependently to promote axon guidance by regulating the MIG-2 GTPase.
SYD-1C, UNC-40 (DCC) and SAX-3 (Robo) function interdependently to promote axon guidance by regulating the MIG-2 GTPase.
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DOI：
10.1371/journal.pgen.1005185
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发表时间：
2015-04
期刊：
影响因子：
4.5
通讯作者：
Quinn CC
中科院分区：
文献类型：
--
作者：
Xu Y;Taru H;Jin Y;Quinn CC
在发育过程中，轴突必须整合由多种引导线索及其受体编码的方向信息。轴突导向受体，如DCC-40（DCC）和SAX-3（Robo），可以单独或与其他导向受体组合发挥作用，以调节下游效应物。然而，很少有人知道的分子机制，介导的组合指导受体信号。在这里，我们发现，SAX 40，SAX 3和SYD-1 RhoGAP样蛋白相互依赖地调节C.优雅的我们发现，SYD-1介导了一个独立于β-6（netrin）的β-40活性，以促进腹侧轴突的指导。遗传分析表明，SYD-1在轴突导向中的功能需要α-40和SAX-3的活性。此外，Bax-40和SAX-3的胞质结构域结合SYD-1，SYD-1结合并负调节Bax-2（Rac）GTP酶。我们还发现SYD-1在轴突引导中的功能是由其在遗传学上保守的C亚型介导的，这表明SYD-1在引导中的作用不同于其先前描述的在突触发生和轴突特化中的作用。我们的观察揭示了一种分子机制，可以允许两个指导受体相互依赖地发挥作用，以调节一个共同的下游效应器，为整合指导信号提供了一种潜在的手段。神经系统由复杂的轴突连接网络组成。这个网络是在发育过程中形成的，当轴突导航到它们的目标区域时。轴突导航需要多个信号通路来检测和响应细胞外引导线索。许多指导线索，受体和信号通路已经确定。然而，很少有人知道如何编码的信息由不同的指导线索相结合，以达到一个方向性的反应。这一过程的关键部分可能涉及组合受体信号传导，即不同的指导受体相互结合起作用。然而，组合受体信号传导的基础机制仍然是未知的。In C.在线虫中，腹侧轴突导向由NTA-40（DCC）和SAX-3（Robo）导向受体介导。在这里，我们使用遗传和生物化学分析来确定一种分子机制，可以介导的组合信号转导，涉及到α-40，SAX-3和RhoGAP样蛋白SYD-1。
During development, axons must integrate directional information encoded by multiple guidance cues and their receptors. Axon guidance receptors, such as UNC-40 (DCC) and SAX-3 (Robo), can function individually or combinatorially with other guidance receptors to regulate downstream effectors. However, little is known about the molecular mechanisms that mediate combinatorial guidance receptor signaling. Here, we show that UNC-40, SAX-3 and the SYD-1 RhoGAP-like protein function interdependently to regulate the MIG-2 (Rac) GTPase in the HSN axon of C. elegans. We find that SYD-1 mediates an UNC-6 (netrin) independent UNC-40 activity to promote ventral axon guidance. Genetic analysis suggests that SYD-1 function in axon guidance requires both UNC-40 and SAX-3 activity. Moreover, the cytoplasmic domains of UNC-40 and SAX-3 bind to SYD-1 and SYD-1 binds to and negatively regulates the MIG-2 (Rac) GTPase. We also find that the function of SYD-1 in axon guidance is mediated by its phylogenetically conserved C isoform, indicating that the role of SYD-1 in guidance is distinct from its previously described roles in synaptogenesis and axonal specification. Our observations reveal a molecular mechanism that can allow two guidance receptors to function interdependently to regulate a common downstream effector, providing a potential means for the integration of guidance signals. The nervous system is comprised of a complex network of axonal connections. This network is formed during development, when axons navigate to their target regions. Axon navigation requires multiple signaling pathways to detect and respond to extracellular guidance cues. Many of the guidance cues, receptors and signaling pathways have been identified. However, little is known about how the information encoded by different guidance cues is combined to arrive at a directional response. A key part of how this occurs is likely to involve combinatorial receptor signaling, when different guidance receptors work in combination with each other. However, the mechanisms that underlie combinatorial receptor signaling remain mostly unknown. In C. elegans, ventral axon guidance is mediated by the UNC-40 (DCC) and SAX-3 (Robo) guidance receptors. Here, we use genetic and biochemical analysis to identify a molecular mechanism that can mediate combinatorial signaling involving UNC-40, SAX-3 and the RhoGAP-like protein SYD-1.
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