Sonic hedgehog induces response of commissural axons to Semaphorin repulsion during midline crossing
Sonic hedgehog induces response of commissural axons to Semaphorin repulsion during midline crossing
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DOI：
10.1038/nn.2457
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发表时间：
2010-01-01
影响因子：
25
通讯作者：
Zou, Yimin
中科院分区：
文献类型：
--
作者：
Parra, Liseth M.;Zou, Yimin
寻路轴突改变了对中间目标的引导线索的反应。在中线交叉过程中，脊髓连合轴突获得对3类信号素和狭缝的反应，后者调节它们的底板出口，并将它们的交叉后轨迹限制在一条纵向通路中。我们发现，Sonic Hedgehog(Shh)可以激活交叉前轴突对信号素的排斥反应。用抗Shh，5e1的单抗阻断Shh的功能，在‘开卷’外植体中，或通过在连合神经元中表达显性-阴性形式的Patted-1，ptch1(Delta Loop2)，或Smomoothed(Smo)shRNA结构，导致严重的引导缺陷，包括在底板内停滞和打结，再交叉，随机的前后投影和交叉后超射，使人想起Neuropilin-2突变胚胎。增强交叉前轴突的蛋白激酶A活性可减少Shh诱导的信号素排斥，并导致交叉后轴突的严重中线停顿和超射/漂移。因此，形态原Shh可以作为轴突引导反应的开关。
Pathfinding axons change responses to guidance cues at intermediate targets. During midline crossing, spinal cord commissural axons acquire responsiveness to class 3 Semaphorins and Slits, which regulate their floor plate exit and restrict their post-crossing trajectory into a longitudinal pathway. We found that Sonic Hedgehog (Shh) could activate the repulsive response of pre-crossing axons to Semaphorins. Blocking Shh function with a monoclonal antibody to Shh, 5E1, in 'open-book' explants or by expressing a dominant-negative form of Patched-1, Ptch1(Delta loop2), or a Smoothened (Smo) shRNA construct in commissural neurons resulted in severe guidance defects, including stalling and knotting inside the floor plate, recrossing, randomized anterior-posterior projection and overshooting after crossing, reminiscent of Neuropilin-2 mutant embryos. Enhancing protein kinase A activity in pre-crossing axons diminished Shh-induced Semaphorin repulsion and caused profound midline stalling and overshooting/wandering of post-crossing axons. Therefore, a morphogen, Shh, can act as a switch of axon guidance responses.