Axon Regeneration Is Regulated by Ets-C/EBP Transcription Complexes Generated by Activation of the cAMP/Ca2+ Signaling Pathways.
Axon Regeneration Is Regulated by Ets-C/EBP Transcription Complexes Generated by Activation of the cAMP/Ca2+ Signaling Pathways.
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DOI：
10.1371/journal.pgen.1005603
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发表时间：
2015-10
期刊：
影响因子：
4.5
通讯作者：
Matsumoto K
中科院分区：
文献类型：
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作者：
Li C;Hisamoto N;Matsumoto K
特定神经元在损伤后再生轴突的能力受细胞内在再生途径的支配。在秀丽线虫中，JNK和p38MAPK通路对轴突再生具有重要作用。轴索损伤诱导编码受体酪氨酸激酶的SVH-2基因表达，SVH-1生长因子刺激SVH-2基因的表达导致JNK通路的激活。在这里，我们确定与哺乳动物ETS和C/EBP相关的Ets-4和CEBP-1分别是轴突损伤后SVH-2表达的转录激活因子。Ets-4和CEBP-1分别位于cAMP和Ca~(2+)-p38 MAPK通路下游。我们发现，依赖于PKA的Ets-4的磷酸化促进了它与CEBP-1的复合体的形成。此外，激活svh-2表达还需要cAMP和钙信号通路的激活。因此，cAMP/Ca~(2+)信号通路协同激活JNK通路，进而促进轴突再生。轴突在损伤后再生的能力受细胞内在再生途径的支配。在线虫中，JNK和p38MAPK通路在轴突再生中起着重要作用。JNK通路被生长因子SVH-1激活，生长因子SVH-1通过其受体SVH-2发出信号。已知SVH-2基因的表达是针对轴突损伤而诱导的，然而这种诱导的分子机制尚不清楚。在这里，我们证明了轴突损伤诱导SVH-2表达涉及转录因子Ets-4和CEBP-1，它们分别位于cAMP和Ca~(2+)-p38 MAPK通路的下游。我们的结果表明，这两条损伤信号通路汇聚在一起，调节SVH-2基因的表达，从而促进轴突再生。
The ability of specific neurons to regenerate their axons after injury is governed by cell-intrinsic regeneration pathways. In Caenorhabditis elegans, the JNK and p38 MAPK pathways are important for axon regeneration. Axonal injury induces expression of the svh-2 gene encoding a receptor tyrosine kinase, stimulation of which by the SVH-1 growth factor leads to activation of the JNK pathway. Here, we identify ETS-4 and CEBP-1, related to mammalian Ets and C/EBP, respectively, as transcriptional activators of svh-2 expression following axon injury. ETS-4 and CEBP-1 function downstream of the cAMP and Ca2+–p38 MAPK pathways, respectively. We show that PKA-dependent phosphorylation of ETS-4 promotes its complex formation with CEBP-1. Furthermore, activation of both cAMP and Ca2+ signaling is required for activation of svh-2 expression. Thus, the cAMP/Ca2+ signaling pathways cooperatively activate the JNK pathway, which then promotes axon regeneration. An axon’s ability to regenerate after injury is governed by cell-intrinsic regeneration pathways. In C. elegans, the JNK and p38 MAPK pathways play an important role in axon regeneration. The JNK pathway is activated by growth factor SVH-1, which signals through its receptor SVH-2. It is known that expression of the svh-2 gene is induced in response to axonal injury, however the molecular mechanisms underlying this induction have been unknown. Here, we demonstrate that induction of svh-2 expression in response to axon injury involves the transcription factors ETS-4 and CEBP-1, which function downstream of the cAMP and Ca2+–p38 MAPK pathways, respectively. Our results suggest that these two injury-signaling pathways converge to regulate expression of the svh-2 gene and thereby promote axon regeneration.