Npn-1 contributes to axon-axon interactions that differentially control sensory and motor innervation of the limb.
Npn-1 contributes to axon-axon interactions that differentially control sensory and motor innervation of the limb.
复制标题
DOI：
10.1371/journal.pbio.1001020
复制
发表时间：
2011-02
期刊：
影响因子：
9.8
通讯作者：
Huber AB
中科院分区：
文献类型：
--
作者：
Huettl RE;Soellner H;Bianchi E;Novitch BG;Huber AB
复杂运动行为的启动、执行和完成依赖于精确整合的神经回路，这些神经回路由激活四肢肌肉的运动通路和向运动神经元提供反馈的感觉传入组成。这些预测在发展过程中形成紧密的时间和空间邻近，但协调这些过程的分子机制和线索还没有得到很好的理解。使用脊髓运动神经元或背根神经节（DRG）感觉神经元中轴突导向受体Neuropilin-1（Npn-1）的细胞类型特异性消融，我们探索了该信号通路对纠正肢体神经支配的贡献。我们发现，Npn-1控制两个预测和介导的轴突间通信的成束。从感觉神经元中去除Npn-1导致感觉轴突的去束，并且令人惊讶地，也导致运动轴突的去束。此外，这两个异型轴突群体之间的紧密耦合被提升，感觉纤维现在领导脊神经投射。这些发现被部分感觉神经元的遗传消除所证实，这会导致肢体运动投射的去束化。从运动神经元中删除Npn-1会导致远端肢体运动轴突的严重解束和背腹侧寻路错误，而肢体感觉轨迹的生长和成束仍然不受影响。然而，运动神经元的遗传消除揭示了感觉轴突只需要运动轴突的最小支架来建立它们在远端肢体中的投射。因此，运动和感觉轴突是相互依赖的，彼此产生的轨迹和相互作用的一部分，通过Npn-1介导的束之前和内的神经丛区域的四肢。在胚胎发育期间，生长中的轴突与其周边目标建立复杂的神经网络，这一过程为复杂行为奠定了基础。例如，当在外周肢体中连接适当的回路时，来自脊髓的运动轴突和来自背根神经节的感觉轴突会聚在脊神经中。在这里，它们混合在一起，然后在到达神经丛区域之前被分类，神经丛区域是它们到达肢体的关键背腹选择点。在这项研究中，我们分析了轴突导向受体Neuropilin-1（Npn-1）的贡献，以确定轴突如何选择它们的路径，它们能够保持正确的路径，以及它如何影响脊髓感觉轴突和运动轴突之间的相互作用。我们发现，当Npn-1从感觉神经元中消除时，感觉和运动轴突都从它们正确的神经束中“脱轨”，并且这些轴突群体之间的紧密耦合出现断裂。然而，运动神经元中的Npn-1的丢失仅在运动轴突中导致轴突捆绑和寻路错误的损害，而感觉轴突不受影响。对感觉神经元或运动神经元的基因消融研究证实了脊髓突起的相互依赖性和特异性。这些结果揭示了Npn-1在控制特定的轴突-轴突相互作用中的作用，这些轴突-轴突相互作用导致形成到肢体的适当的脊髓感觉-运动轨迹。此外，他们认为，存在的最小数量的感觉或运动轴突是足够的形成正确的脊髓投射。
The initiation, execution, and completion of complex locomotor behaviors are depending on precisely integrated neural circuitries consisting of motor pathways that activate muscles in the extremities and sensory afferents that deliver feedback to motoneurons. These projections form in tight temporal and spatial vicinities during development, yet the molecular mechanisms and cues coordinating these processes are not well understood. Using cell-type specific ablation of the axon guidance receptor Neuropilin-1 (Npn-1) in spinal motoneurons or in sensory neurons in the dorsal root ganglia (DRG), we have explored the contribution of this signaling pathway to correct innervation of the limb. We show that Npn-1 controls the fasciculation of both projections and mediates inter-axonal communication. Removal of Npn-1 from sensory neurons results in defasciculation of sensory axons and, surprisingly, also of motor axons. In addition, the tight coupling between these two heterotypic axonal populations is lifted with sensory fibers now leading the spinal nerve projection. These findings are corroborated by partial genetic elimination of sensory neurons, which causes defasciculation of motor projections to the limb. Deletion of Npn-1 from motoneurons leads to severe defasciculation of motor axons in the distal limb and dorsal-ventral pathfinding errors, while outgrowth and fasciculation of sensory trajectories into the limb remain unaffected. Genetic elimination of motoneurons, however, revealed that sensory axons need only minimal scaffolding by motor axons to establish their projections in the distal limb. Thus, motor and sensory axons are mutually dependent on each other for the generation of their trajectories and interact in part through Npn-1-mediated fasciculation before and within the plexus region of the limbs. During embryonic development, growing axons establish intricate neural networks with their peripheral targets, a process that builds the basis for complex behaviors. While wiring up the proper circuits in peripheral limbs, for example, motor axons from the spinal cord and sensory axons from the dorsal root ganglia converge in the spinal nerve. Here, they intermingle and are subsequently sorted before reaching the plexus region, the pivotal dorsal-ventral choice point on their path to the limb. In this study, we analyzed the contribution of the axon guidance receptor Neuropilin-1 (Npn-1) to determine how axons choose their path, how well they are able to maintain their correct path, and how it influences the interactions between spinal sensory axons and motor axons. We find that when Npn-1 is eliminated from sensory neurons, both sensory and motor axons are “derailed” from their correct nerve bundles, and there is a break in the tight coupling between these axonal populations. Loss of Npn-1 in motoneurons, however, leads to impairments in axon bundling and pathfinding errors only in motor axons, while sensory axons remain unaffected. Genetic ablation studies of either sensory or motor neurons corroborate the results on the mutual dependency and specificity of the outgrowing spinal projections. These results reveal a role for Npn-1 in controlling specific axon-axon interactions that lead to formation of proper spinal sensory-motor trajectories to the limb. Furthermore, they suggest that the presence of minimal numbers of sensory or motor axons is sufficient for the formation of correct spinal projections.
登录
查看更多内容
影响因子：
2.7
作者：
Eberhart, J;Swartz, ME;Krull, CD
通讯作者：
Krull, CD
影响因子：
2.7
作者：
Pietri, T;Eder, O;Dufour, S
通讯作者：
Dufour, S
影响因子：
1.5
作者：
Brockschniedier, Damian;Pechmann, Yvonne;Riethmacher, Dieter
通讯作者：
Riethmacher, Dieter
影响因子：
3.4
作者：
Haupt, Corinna;Kloos, Karina;Huber, Andrea B.
通讯作者：
Huber, Andrea B.
影响因子：
16.2
作者：
Huber, AB;Kania, A;Kolodkin, AL
通讯作者：
Kolodkin, AL