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Neuron. 2007 Feb 1;53(3):387-97.

NMDA-receptor activation induces calpain-mediated beta-catenin cleavages for triggering gene expression.

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Graduate School of Biostudies, Kyoto University, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan.


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 immediate-early 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-catenin-dependent 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.

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