Modulation of Semaphorin3A activity by p75 neurotrophin receptor influences peripheral axon Patterning
Modulation of Semaphorin3A activity by p75 neurotrophin receptor influences peripheral axon Patterning
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DOI：
10.1523/jneurosci.3373-07.2007
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发表时间：
2007-11-21
影响因子：
5.3
通讯作者：
Behar, Oded
中科院分区：
文献类型：
--
作者：
Ben-Zvi, Ayal;Ben-Gigi, Liat;Behar, Oded
p75神经营养因子受体（p75（NTR））与多种配体和辅助受体相互作用。它被认为是介导髓鞘生长抑制作为Nogo受体复合物的一部分，除了它的其他作用。然而，奇怪的是，p75（外显子III）（-/-）突变胚胎的外周轴突严重发育不良。这种轴突生长的抑制可能是p75（NTR）突变神经元中轴突伸长缺陷的结果。在这里，我们表明，p75（外显子III-/-）DRG神经元过敏的排斥分子Semaphorin 3A（Sema 3A）。神经生长因子调节Sema 3A活性同样好，在p75（NTR）突变体和野生型神经元，表明p75（NTR）突变体神经元的超敏反应可能是不相关的，他们的神经生长因子受体活性。Neuropilin 1和p75（NTR）部分共定位于DRG生长锥。在Sema 3A刺激后，共定位的程度显著增加，特别是在与Sema 3A受体复合物活化相关的簇中。免疫共沉淀研究表明，p75（NTR）直接与Sema 3A受体Neuropilin 1和PlexinA 4相互作用。当与Neuropilin 1和PlexinA 4共表达时，p75（NTR）减少这两种受体组分之间的相互作用。最后，p75（NTR）/Sema 3A双突变体胚胎显示出与Sema 3A缺失小鼠中观察到的相似的生长。这些数据表明，p75（NTR）是Sema 3A活性的一个重要的功能性调节剂，并且在没有p75（NTR）的情况下，对Sema 3A的过度敏感导致感觉神经支配的严重减少。我们的研究结果还表明，虽然抑制p75（NTR）在中枢神经系统损伤可能会增强神经再生髓鞘相关蛋白的抑制所导致的，它也可能通过其调制Sema 3A抑制神经再生。
The p75 neurotrophin receptor (p75(NTR)) interacts with multiple ligands and coreceptors. It is thought to mediate myelin growth inhibition as part of the Nogo receptor complex, in addition to its other roles. Paradoxically, however, peripheral axons of p75(ExonIII) (-/-) mutant embryos are severely stunted. This inhibition of axon growth may be a result of neurite elongation defects in p75(NTR) mutant neurons. Here, we show that p75(ExonIII -/-) DRG neurons are hypersensitive to the repellent molecule Semaphorin3A (Sema3A). NGF modulates Sema3A activity equally well in both the p75(NTR) mutant and wild-type neurons, indicating that the hypersensitivity of p75(NTR) mutant neurons is probably not related to their NGF receptor activity. Neuropilin1 and p75(NTR) partially colocalize in DRG growth cones. After Sema3A stimulation, the degree of colocalization is dramatically increased, particularly in clusters associated with Sema3A receptor complex activation. Coimmunoprecipitation studies show that p75(NTR) interacts directly with the Sema3A receptors Neuropilin1 and PlexinA4. When coexpressed with both Neuropilin1 and PlexinA4, p75(NTR) reduces the interaction between these two receptor components. Finally, p75(NTR)/Sema3A double-mutant embryos show growth similar to that observed in Sema3A-null mice. These data indicate that p75(NTR) is an important functional modulator of Sema3A activity and that, in the absence of p75(NTR), oversensitivity to Sema3A leads to severe reduction in sensory innervation. Our results also suggest that while inhibition of p75(NTR) in CNS injury may enhance nerve regeneration resulting from the inhibition of myelin-associated protein, it may also inhibit nerve regeneration through its modulation of Sema3A.