NMDA-receptor activation induces calpain-mediated beta-catenin cleavages for triggering gene expression.
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.
Abe
Kentaro
K
Graduate School of Biostudies, Kyoto University, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan.
Takeichi
Masatoshi
M
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002154:Calpain / Q000502:physiology*; D002478:Cells, Cultured; D015870:Gene Expression / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000502:physiology; D014178:Translocation, Genetic; D051176:beta Catenin / Q000378:metabolism*
D016194:Receptors, N-Methyl-D-Aspartate; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3; D002154:Calpain