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Molecular and Cellular Biology, March 2008, p. 1515-1527, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.02227-06
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Wnt Pool of Glycogen Synthase Kinase 3β Is Critical for Trophic-Deprivation-Induced Neuronal Death{triangledown}

Vesa Hongisto,1 Jenni C. Vainio,1 Róisín Thompson,2 Michael J. Courtney,1,2 and Eleanor T. Coffey1*

Turku Centre for Biotechnology, Turku University and Åbo Akademi University, Turku, Finland,1 A. I. Virtanen Institute, University of Kuopio, Kuopio, Finland2

Received 28 November 2006/ Returned for modification 3 January 2007/ Accepted 10 December 2007

Glycogen synthase kinase 3 (GSK-3) is implicated in neuronal death through a causal role, and precise mechanisms have not been unambiguously defined. We show that short hairpin RNA (shRNA) knockdown of GSK-3β, but not GSK-3{alpha}, protects cerebellar granule neurons from trophic-deprivation-induced death. Using compartment-targeted inhibitors of the Wnt-regulated GSK-3 pool, NLS-FRAT1, NES-FRAT1, and axin-GSK-3-interacting domain (axin-GID), we locate proapoptotic GSK-3 action to the cytosol and regulation of Bim protein turnover despite constitutive cycling of GSK-3 between the cytosol and nucleus, revealed by leptomycin B. We examine the importance of Ser21/9 (GSK-3{alpha}/β) phosphorylation on proapoptotic GSK-3 function. Neurons isolated from GSK-3{alpha}/βS21A/S9A knock-in mice survive normally and are fully sensitive to trophic-deprivation-induced death. Nonetheless, inhibition of GSK-3 catalytic activity with lithium or SB216763 protects GSK-3{alpha}/βS21A/S9A neurons from death. This indicates that dephosphorylation of GSK-3β/Ser9 and GSK-3{alpha}/Ser21 is insufficient for GSK-3 proapoptotic function and that another level of regulation is required. Gel filtration reveals a stress-induced loss of neuronal GSK-3β from a high-molecular-mass complex with a concomitant decrease in axin-bound GSK-3β. These data imply that Wnt-regulated GSK-3β plays a nonredundant role in trophic-deprivation-induced death of neurons.

* Corresponding author. Mailing address: Turku Centre for Biotechnology, Turku University and Åbo Akademi University, BioCity, Tykistokatu 6, Turku FIN-20521, Finland. Phone: 358-2-3338605. Fax: 358-2-3338000. E-mail: ecoffey{at}btk.fi

{triangledown} Published ahead of print on 14 January 2008.

Molecular and Cellular Biology, March 2008, p. 1515-1527, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.02227-06
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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