p75-mediated NF-κB activation enhances the survival response of developing sensory neurons to nerve growth factor
p75-mediated NF-κB activation enhances the survival response of developing sensory neurons to nerve growth factor
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DOI：
10.1006/mcne.1999.0770
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发表时间：
1999-07-01
影响因子：
3.5
通讯作者：
Davies, AM
中科院分区：
文献类型：
--
作者：
Hamanoue, M;Middleton, G;Davies, AM
我们研究了转录因子NF-κ B B是否通过操纵胚胎小鼠三叉神经节神经生长因子（NGF）依赖性感觉神经元中NF-κ B B的激活在调节神经元存活中发挥作用。p65或p50 NF-κ B亚基的过表达导致NF-κ B活化，并与NGF一样有效地促进体外存活。在p65/p50过表达的神经元中，超阻遏物I κ B-α蛋白的表达阻止了NF-κ B的激活，并导致神经元像NGF剥夺的神经元一样迅速死亡。NGF处理也激活NF-κ B，用超阻遏物I κ B-α阻止这种激活降低了NGF存活反应。阻断NGF与p75受体结合的抗体阻止了NGF诱导的NF-κ B活化，并降低了与超阻遏物I κ B-α相同程度的NGF存活反应。与野生型胚胎相比，培养自p65（-/-）胚胎的三叉神经元对NGF的存活反应降低，体内培养的p65（-/-）胚胎三叉神经节中神经元凋亡增加。然而，与p75缺陷的感觉神经元一样，p68缺陷的感觉神经元对BDNF表现出正常的存活反应。这些结果揭示了NF-κ B B在胚胎发育过程中调节神经元存活的作用，并表明，除了良好建立的Trk受体酪氨酸激酶信号级联反应，NGF通过p75介导的途径增强神经元存活。
We have investigated whether the transcription factor NF-kappa B plays a role in regulating neuronal survival by manipulating NF-kappa B activation in the nerve growth factor (NGF)-dependent sensory neurons of the embryonic mouse trigeminal ganglion. Overexpression of either the p65 or the p50 NF-kappa B subunits resulted in NF-kappa B activation and promoted in vitro survival as effectively as NGF. Expression of a superrepressor I kappa B-alpha protein prevented NF-kappa B activation in p65/p50-overexpressing neurons and caused the neurons to die as rapidly as NGF-deprived neurons. NGF treatment also activated NF-kappa B, and preventing this activation with superrepressor I kappa B-alpha reduced the NGF survival response. Antibodies that block binding of NGF to the p75 receptor prevented NGF-induced NF-kappa B activation and reduced the NGF survival response to the same extent as superrepressor I kappa B-alpha. Trigeminal neurons cultured from p65(-/-) embryos showed a reduced survival response to NGF compared with neurons from wild-type embryos and there was increased apoptosis of neurons in the trigeminal ganglia of p65(-/-) embryos in vivo. However, as with p75-deficient sensory neurons, p68-deficient sensory neurons showed a normal survival response to BDNF. These results reveal a role for NF-kappa B in regulating neuronal survival during embryonic development and suggest that in addition to the well-established Trk receptor tyrosine kinase signaling cascade, NGF enhances neuronal survival by signaling via a p75-mediated pathway.