The Death Receptor Antagonist FLIP-L Interacts with Trk and Is Necessary for Neurite Outgrowth Induced by Neurotrophins
The Death Receptor Antagonist FLIP-L Interacts with Trk and Is Necessary for Neurite Outgrowth Induced by Neurotrophins
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DOI：
10.1523/jneurosci.0537-10.2010
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发表时间：
2010-04-28
影响因子：
5.3
通讯作者：
Comella, Joan X.
中科院分区：
文献类型：
--
作者：
Moubarak, Rana S.;Sole, Carme;Comella, Joan X.
FLICE抑制蛋白（FLIP）是一种内源性抑制剂，可通过激活死亡受体来触发信号通路。在这里，我们揭示了一种新的生物功能的长形式的FLIP（FLIP-L）在神经元分化，这可以从其抗凋亡的作用。我们发现FLIP-L在小鼠胚胎神经系统的不同区域表达。在不同阶段的小鼠脑切片的免疫组织化学显示，在神经元中，FLIP在胚胎神经元发育的早期（胚胎第16天）表达，并在后期（出生后第5-15天）减少，此时其表达基本上在神经胶质细胞中检测到。FLIP-L过表达显著增强运动神经元、上级颈神经节神经元和PC 12细胞中神经营养因子诱导的神经突生长。相反，通过特异性RNA干扰下调FLIP-L蛋白水平显著减少神经突生长，即使在适当的神经营养因子刺激存在下。此外，当内源性FLIP-L下调时，参与神经突生长调节的两个主要细胞内途径，细胞外信号调节激酶（ERK）和核因子κ B（NF-κ B）的NGF依赖性活化受损，尽管TrkA保持活化。最后，我们证明了FLIP-L与TrkA相互作用，而不是与p75（NTR），在一个神经生长因子依赖的方式，和内源性FLIP-L与TrkB在胚胎第15天的小鼠胚胎全脑裂解液相互作用。总之，我们发现了FLIP-L作为神经营养因子诱导的丝裂原活化蛋白激酶/ERK和NF-κ B介导的发育中神经元轴突生长控制的一个意想不到的关键参与者的新作用。
FLICE-inhibitory protein (FLIP) is an endogenous inhibitor of the signaling pathway triggered by the activation of death receptors. Here, we reveal a novel biological function for the long form of FLIP (FLIP-L) in neuronal differentiation, which can be dissociated from its antiapoptotic role. We show that FLIP-L is expressed in different regions of the mouse embryonic nervous system. Immunohistochemistry of mouse brain sections at different stages reveals that, in neurons, FLIP is expressed early during the embryonic neuronal development (embryonic day 16) and decreases at later stages (postnatal days 5-15), when its expression is essentially detected in glial cells. FLIP-L overexpression significantly enhances neurotrophin-induced neurite outgrowth in motoneurons, superior cervical ganglion neurons, and PC12 cells. Conversely, the downregulation of FLIP-L protein levels by specific RNA interference significantly reduces neurite outgrowth, even in the presence of the appropriate neurotrophin stimulus. Moreover, NGF-dependent activation of two main intracellular pathways involved in the regulation of neurite outgrowth, extracellular signal-regulated kinases (ERKs) and nuclear factor kappa B (NF-kappa B), is impaired when endogenous FLIP-L is downregulated, although TrkA remains activated. Finally, we demonstrate that FLIP-L interacts with TrkA, and not with p75(NTR), in an NGF-dependent manner, and endogenous FLIP-L interacts with TrkB in whole-brain lysates from embryonic day 15 mice embryos. Altogether, we uncover a new role for FLIP-L as an unexpected critical player in neurotrophin-induced mitogen-activated protein kinase/ERK- and NF-kappa B-mediated control of neurite growth in developing neurons.