p190RhoGAP Filters Competing Signals to Resolve Axon Guidance Conflicts

Bonanomi Dario; Valenza Fabiola; Chivatakarn Onanong; Sternfeld Matthew J.; Driscoll Shawn P.; Aslanian Aaron; Lettieri Karen; Gullo Miriam; Badaloni Aurora; Lewcock Joseph W.; Hunter Tony; Pfaff Samuel L.

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p190RhoGAP Filters Competing Signals to Resolve Axon Guidance Conflicts

机译：P190RHOGAP过滤器竞争信号以解决Axon Guidance冲突

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The rich functional diversity of the nervous system is founded in the specific connectivity of the underlying neural circuitry. Neurons are often preprogrammed to respond to multiple axon guidance signals because they use sequential guideposts along their pathways, but this necessitates a strict spatiotemporal regulation of intracellular signaling to ensure the cues are detected in the correct order. We performed a mouse mutagenesis screen and identified the Rho GTPase antagonist p190RhoGAP as a critical regulator of motor axon guidance. Rather than acting as a compulsory signal relay, p190RhoGAP uses a non-conventional GAP-independent mode to transiently suppress attraction to Netrin-1 while motor axons exit the spinal cord. Once in the periphery, a subset of axons requires p190RhoGAP-mediated inhibition of Rho signaling to target specific muscles. Thus, the multifunctional activity of p190RhoGAP emerges from its modular design. Our findings reveal a cellintrinsic gate that filters conflicting signals, establishing temporal windows of signal detection.

机译：神经系统的丰富功能多样性成立于底层神经电路的特定连接。神经元通常预编程以响应多个轴突引导信号，因为它们沿着它们的途径使用序贯导向，但这需要严格的细胞内信号传导，以确保以正确的顺序检测线索。我们进行了一个小鼠诱变筛网，并将Rho GTPase拮抗剂P190RHoGap作为电动机轴突引导的临界调节器鉴定为临界调节器。 P190RHOGAP而不是充当强制信号继电器，而是使用非传统间隙无关模式至瞬时抑制到Netrin-1的吸引力，而马达轴突出局脊髓。一旦在外围，轴突子子集需要P190RHOGAP介导的RHO信号传导至靶向特定肌肉。因此，P190RHOGAP的多功能活动从其模块化设计中出现。我们的调查结果显示了一种筛选互连信号的Cellintrinsic门，建立信号检测的时间窗口。

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《Neuron》 |2019年第3期|共28页
作者
Bonanomi Dario; Valenza Fabiola; Chivatakarn Onanong; Sternfeld Matthew J.; Driscoll Shawn P.; Aslanian Aaron; Lettieri Karen; Gullo Miriam; Badaloni Aurora; Lewcock Joseph W.; Hunter Tony; Pfaff Samuel L.;
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Salk Inst Biol Studies Gene Express Lab 10010 North Torrey Pines La Jolla CA 92037 USA;

Ist Sci San Raffaele Div Neurosci Via Olgettina 60 I-20132 Milan Italy;

Salk Inst Biol Studies Gene Express Lab 10010 North Torrey Pines La Jolla CA 92037 USA;

Salk Inst Biol Studies Gene Express Lab 10010 North Torrey Pines La Jolla CA 92037 USA;

Salk Inst Biol Studies Gene Express Lab 10010 North Torrey Pines La Jolla CA 92037 USA;

Salk Inst Biol Studies Mol &

Cell Biol Lab 10010 North Torrey Pines La Jolla CA 92037 USA;

Salk Inst Biol Studies Gene Express Lab 10010 North Torrey Pines La Jolla CA 92037 USA;

Salk Inst Biol Studies Gene Express Lab 10010 North Torrey Pines La Jolla CA 92037 USA;

Ist Sci San Raffaele Div Neurosci Via Olgettina 60 I-20132 Milan Italy;

Salk Inst Biol Studies Gene Express Lab 10010 North Torrey Pines La Jolla CA 92037 USA;

Salk Inst Biol Studies Mol &

Cell Biol Lab 10010 North Torrey Pines La Jolla CA 92037 USA;

Salk Inst Biol Studies Gene Express Lab 10010 North Torrey Pines La Jolla CA 92037 USA;

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4. p190RhoGAP Filters Competing Signals to Resolve Axon Guidance Conflicts [J] . Bonanomi Dario, Valenza Fabiola, Chivatakarn Onanong, Neuron . 2019,第3期

机译：P190RHOGAP过滤器竞争信号以解决Axon Guidance冲突
5. The microtubule plus-end-tracking protein TACC3 promotes persistent axon outgrowth and mediates responses to axon guidance signals during development [J] . Burcu Erdogan, Garrett M. Cammarata, Eric J. Lee, Neural development . 2017,第1期

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6. Wnt5a induces simultaneous cortical axon outgrowth and repulsive axon guidance through distinct signaling mechanisms. [J] . Li L, Hutchins BI, Kalil K The Journal of Neuroscience: The Official Journal of the Society for Neuroscience . 2009,第18期

机译：Wnt5a通过不同的信号传导机制同时诱导皮质轴突的生长和排斥轴突的引导。
7. Resolving goal conflicts via argumentation-based analysis of competing hypotheses [C] . Murukannaiah Pradeep K., Kalia Anup K., Telangy Pankaj R., IEEE International Requirements Engineering Conference . 2015

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8. An axon's journey to find its path: In vivo characterization of the modulators and effectors of the Rac GTPase signaling pathway involved in axon guidance . [D] . Demarco, Rafael Senos. 2011

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9. The microtubule plus-end-tracking protein TACC3 promotes persistent axon outgrowth and mediates responses to axon guidance signals during development [O] . Burcu Erdogan, Garrett M. Cammarata, Eric J. Lee, 2017

机译：微管正末尾追踪蛋白TACC3促进持续的轴突生长并在发育过程中介导对轴突指导信号的反应
10. Novel mutations affecting axon guidance in zebrafish and a role for plexin signalling in the guidance of trigeminal and facial nerve axons [O] . Hideomi Tanaka, Ryu Maeda, Wataru Shoji, 2007

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p190RhoGAP Filters Competing Signals to Resolve Axon Guidance Conflicts

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