NMDA-receptor activation induces calpain-mediated β-catenin cleavages for triggering gene expression
NMDA-receptor activation induces calpain-mediated β-catenin cleavages for triggering gene expression
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DOI：
10.1016/j.neuron.2007.01.016
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发表时间：
2007-02-01
期刊：
影响因子：
16.2
通讯作者：
Takeichi, Masatoshi
中科院分区：
文献类型：
--
作者：
Abe, Kentaro;Takeichi, Masatoshi
经典的Wnt-β-连环蛋白信号通路对于多种发育现象以及对于致癌作用是重要的。在这里，我们表明，在海马神经元中，NMDA受体依赖性激活钙蛋白酶诱导β-连环蛋白的N端裂解，产生稳定的，截断的形式。这些β-连环蛋白片段在细胞核中积累并诱导Tcf/Lef-dependent基因转录。我们确定了Fosl 1，一个即时早期基因，作为该信号通路的靶点。此外，小鼠的探索行为导致海马神经元中β-连环蛋白的类似裂解以及Tcf信号通路的激活。钙蛋白酶抑制剂抑制β-连环蛋白裂解和Tcf依赖的基因转录。这些发现揭示了除了经典的Wnt-β-catenin途径之外，β-catenindependent信号传导的另一种途径，并表明这种其他途径可能在活性依赖性基因表达中发挥重要作用。
The canonical Wnt-beta-catenin signaling pathway is important for a variety of developmental phenomena as well as for carcinogenesis. Here, we show that, in hippocampal neurons, NMDA-receptor-dependent activation of calpain induced the cleavage of beta-catenin at the N terminus, generating stable, truncated forms. These beta-catenin fragments accumulated in the nucleus and induced Tcf/Lef-dependent gene transcription. We identified Fosl1, one of the immediateearly genes, as a target of this signaling pathway. In addition, exploratory behavior by mice resulted in a similar cleavage of beta-catenin, as well as activation of the Tcf signaling pathway, in hippocampal neurons. Both beta-catenin cleavage and Tcf-dependent gene transcription were suppressed by calpain inhibitors. These findings reveal another pathway for beta-catenindependent signaling, in addition to the canonical Wnt-beta-catenin pathway, and suggest that this other pathway could play an important role in activity-dependent gene expression.