Axotomy-induced HIF-serotonin signalling axis promotes axon regeneration in C. elegans.
Axotomy-induced HIF-serotonin signalling axis promotes axon regeneration in C. elegans.
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DOI：
10.1038/ncomms10388
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发表时间：
2016-01-21
影响因子：
16.6
通讯作者：
Matsumoto K
中科院分区：
文献类型：
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作者：
Alam T;Maruyama H;Li C;Pastuhov SI;Nix P;Bastiani M;Hisamoto N;Matsumoto K
损伤后轴突再生能力的分子机制仍然知之甚少。在这里，我们表明，在秀丽隐杆线虫，轴突切断诱导异位表达的5-羟色胺（5-HT）在轴突切断的非神经元通过HIF-1，缺氧诱导的转录因子，和5-HT随后促进轴突再生的自分泌信号通过SER-7 5-HT受体。此外，我们确定了rhgf-1和rga-5基因，分别编码同源的RhoGEF和RhoGAP，作为轴突再生的调节剂。我们证明SER-7启动的一条通路作用于C.线虫RhoA同源物RHO-1在神经元再生中的作用，其通过G12 α和RHGF-1发挥作用。在该途径中，RHO-1抑制二酰甘油激酶，导致二酰甘油增加。SER-7还通过激活环AMP（cAMP）信号通路促进轴突再生。因此，HIF-1介导的5-HT信号转导激活通过激活RhoA和cAMP途径促进轴突再生。 损伤后轴突再生的分子机制知之甚少。在这里，作者表明，在C。在elegans中，HIF-1转录因子诱导切断的"非轴突能"神经元中5-羟色胺的异位合成，并且5-羟色胺激活下游信号通路，导致轴突再生。
The molecular mechanisms underlying the ability of axons to regenerate after injury remain poorly understood. Here we show that in Caenorhabditis elegans, axotomy induces ectopic expression of serotonin (5-HT) in axotomized non-serotonergic neurons via HIF-1, a hypoxia-inducible transcription factor, and that 5-HT subsequently promotes axon regeneration by autocrine signalling through the SER-7 5-HT receptor. Furthermore, we identify the rhgf-1 and rga-5 genes, encoding homologues of RhoGEF and RhoGAP, respectively, as regulators of axon regeneration. We demonstrate that one pathway initiated by SER-7 acts upstream of the C. elegans RhoA homolog RHO-1 in neuron regeneration, which functions via G12α and RHGF-1. In this pathway, RHO-1 inhibits diacylglycerol kinase, resulting in an increase in diacylglycerol. SER-7 also promotes axon regeneration by activating the cyclic AMP (cAMP) signalling pathway. Thus, HIF-1-mediated activation of 5-HT signalling promotes axon regeneration by activating both the RhoA and cAMP pathways. The molecular mechanism of axon regeneration after injury is poorly understood. Here the authors show that in C. elegans, the HIF-1 transcription factor induces ectopic synthesis of serotonin in severed ‘non-serotonergic' neurons and that serotonin activates downstream signaling pathways leading to axon regeneration.