Netrin-1 acts as a survival factor via its receptors UNC5H and DCC
Netrin-1 acts as a survival factor via its receptors UNC5H and DCC
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DOI：
10.1093/emboj/20.11.2715
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发表时间：
2001-06-01
期刊：
影响因子：
11.4
通讯作者：
Mehlen, P
中科院分区：
文献类型：
--
作者：
Llambi, F;Causeret, F;Mehlen, P
膜受体DCC和UNC5H作为Netrin-1的受体，在轴突引导和神经元迁移中起着至关重要的作用。DCC也被认为是一种依赖受体，可诱导超出netrin-1可获得性的细胞凋亡。在这里，我们证明了Netrin-1受体unc5H(UNCSH1，unc5H2，unc5H3)也是依赖受体，unc5H受体诱导细胞凋亡，但这一作用在Netrin-1的存在下被阻断。此外，我们还证明了在体外，unc5H受体被其胞内区的caspase所切割。这种切割可能导致暴露一段包含在体内诱导细胞死亡所需的死亡结构域的片段。最后，我们提出的证据表明，在神经系统的发育过程中，netrin-1的存在对于维持表达unc5H和DCC的神经元的存活至关重要，特别是在脑干的脑室区域。总之，这些结果证明了netrin-1在神经系统发育过程中的作用，不仅是作为一个指导信号，而且是通过其受体DCC和unc5H作为一个生存因子。
The membrane receptors DCC and UNC5H have been shown to be crucial for axon guidance and neuronal migration by acting as receptors for netrin-1. DCC has also been proposed as a dependence receptor inducing apoptosis in cells that are beyond netrin-1 availability. Here we show that the netrin-1 receptors UNC5H (UNCSH1, UNC5H2, UNC5H3) also act as dependence receptors, UNC5H receptors induce apoptosis, but this effect is blocked in the presence of netrin-1, Moreover, we demonstrate that UNC5H receptors are cleaved in vitro by caspase in their intracellular domains. This cleavage may Lead to the exposure of a fragment encompassing a death domain required for cell death induction in vivo. Finally, we present evidence that during development of the nervous system, the presence of netrin-1 is crucial to maintain survival of UNC5H- and DCC-expressing neurons, especially in the ventricular zone of the brainstem. Altogether, these results argue for a role of netrin-1 during the development of the nervous system, not only as a guidance cue but as a survival factor via its receptors DCC and UNC5H.