p190RhoGAP Filters Competing Signals to Resolve Axon Guidance Conflicts
p190RhoGAP Filters Competing Signals to Resolve Axon Guidance Conflicts
复制标题
DOI：
10.1016/j.neuron.2019.02.034
复制
发表时间：
2019-05-08
期刊：
影响因子：
16.2
通讯作者：
Pfaff, Samuel L.
中科院分区：
文献类型：
--
作者：
Bonanomi, Dario;Valenza, Fabiola;Pfaff, Samuel L.
神经系统丰富的功能多样性是建立在底层神经回路的特定连接上的。神经元通常被预先编程以响应多个轴突的引导信号，因为它们在其路径上使用顺序的路标，但这需要对细胞内信号进行严格的时空调节，以确保以正确的顺序检测到这些信号。我们对小鼠进行了诱变筛选，发现Rho GTPase拮抗剂p190RhoGAP是运动轴突引导的关键调节剂。p190RhoGAP不是作为强制性的信号继电器，而是使用一种非常规的与gap无关的模式，在运动轴突离开脊髓时暂时抑制对Netrin-1的吸引力。一旦进入外周，轴突的一个子集需要p190rhogap介导的Rho信号抑制来靶向特定肌肉。因此，p190RhoGAP的多功能活性源于其模块化设计。我们的发现揭示了一个滤除冲突信号的细胞本征门，建立了信号检测的时间窗口。
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.