Type III neuregulin 1 regulates pathfinding of sensory axons in the developing spinal cord and periphery
Type III neuregulin 1 regulates pathfinding of sensory axons in the developing spinal cord and periphery
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DOI：
10.1242/dev.072306
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发表时间：
2011-11-15
期刊：
影响因子：
4.6
通讯作者：
Flanagan, John G.
中科院分区：
文献类型：
--
作者：
Hancock, Melissa L.;Nowakowski, Dan W.;Flanagan, John G.
感觉轴突必须与中枢和外周目标建立适当的连接。虽然外周线索为神经元生存和指导提供了经典模型，但人们对中枢线索或中枢和外周连接的协调知之甚少。在这里，我们发现 III 型 Nrg1 除了对神经元存活有已知的影响外，还调节轴突寻路。在III型Nrg1(-/-)小鼠中，TrkA(+)伤害感受/温度感受神经元的死亡增加，并且可以通过消除Bax来挽救。在Bax和III型Nrg1双突变体中，在皮肤外周靶点和脊髓中枢靶点中都观察到TrkA(+)神经元的轴突寻路异常。脊髓中的轴突引导表型包括轴突渗透到腹侧区域，通常会被 Sema3A 排斥。因此，来自 III 型 Nrg1(-/-) 小鼠的感觉神经元在体外对 Sema3A 的驱避作用没有反应，这可能至少部分解释了中心投射表型，并证明了 III 型 Nrg1 对神经元引导提示反应的影响。此外，刺激培养的感觉神经元中的 III 型 Nrg1 反向信号传导被发现可以调节 Sema3A 受体神经毡蛋白 1 的轴突水平。这些结果揭示了 III 型 Nrg1 信号传导可以调节神经元对引导信号的反应性的分子机制，并表明 III 型 Nrg1 是正常感觉神经元存活和中枢轴突寻路所必需的。 和外围目标。
Sensory axons must develop appropriate connections with both central and peripheral targets. Whereas the peripheral cues have provided a classic model for neuron survival and guidance, less is known about the central cues or the coordination of central and peripheral connectivity. Here we find that type III Nrg1, in addition to its known effect on neuron survival, regulates axon pathfinding. In type III Nrg1(-/-) mice, death of TrkA(+) nociceptive/thermoreceptive neurons was increased, and could be rescued by Bax elimination. In the Bax and type III Nrg1 double mutants, axon pathfinding abnormalities were seen for TrkA(+) neurons both in cutaneous peripheral targets and in spinal cord central targets. Axon guidance phenotypes in the spinal cord included penetration of axons into ventral regions from which they would normally be repelled by Sema3A. Accordingly, sensory neurons from type III Nrg1(-/-) mice were unresponsive to the repellent effects of Sema3A in vitro, which might account, at least in part, for the central projection phenotype, and demonstrates an effect of type III Nrg1 on guidance cue responsiveness in neurons. Moreover, stimulation of type III Nrg1 back-signaling in cultured sensory neurons was found to regulate axonal levels of the Sema3A receptor neuropilin 1. These results reveal a molecular mechanism whereby type III Nrg1 signaling can regulate the responsiveness of neurons to a guidance cue, and show that type III Nrg1 is required for normal sensory neuron survival and axon pathfinding in both central and peripheral targets.