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Disruption of CREB function in brain leads to neurodegeneration

Nature Genetics volume 31, pages 47–54 (2002)Cite this article

Abstract

Control of cellular survival and proliferation is dependent on extracellular signals and is a prerequisite for ordered tissue development and maintenance. Activation of the cAMP responsive element binding protein (CREB) by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, we disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. Mice with a Crem−/− background and lacking Creb in the central nervous system during development show extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem are disrupted in the postnatal forebrain show progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype is reminiscent of Huntington disease and is consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.

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Figure 1: Generation of mice deficient for CREB in the nervous system.
Figure 2: Cellular integrity is compromised in brains of mice lacking both Creb and Crem.
Figure 3: Normal proliferation, but increased neuronal death, in mice lacking both CREB and CREM in brain.
Figure 4: Neuronal degeneration is initiated between E16.
Figure 5: Neurological and morphological phenotype of Creb1Camkcre4Crem−/− double-mutants.
Figure 6: The striatum and the hippocampus from Creb1Camkcre4Crem−/− double-mutants undergo progressive neurodegeneration.
Figure 7: Astrogliosis in striatum and hippocampus.
Figure 8: Striatal neurodegeneration in Creb1D1creCrem−/−mice.

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Acknowledgements

We thank B. Stride, E. Greiner and K. Unsicker for critical reading of the manuscript; E. Schmid, S. Ridder, A. Klewe-Nebenius, H. Glaser, S. Fehsenfeld, K. Anlag and T. Panek for expert technical assistance and N. Pollet, I. del Barco Barrantes and E. Casanova for stimulating discussions. This work was supported by grants from the European Community and the Deutsches Forschungsgemeinschaft and Forschergruppe (to G.S.). T.L. was supported by fellowships from the Human Frontier Science Program Organization and the Swiss National Science Foundation.

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Author notes

  1. Theo Mantamadiotis

    Present address: Peter MacCallum Cancer Institute, St Andrews Place, East Melbourne, 3002, Australia

  2. Theo Mantamadiotis and Thomas Lemberger: These authors contributed equally to this work.

Authors and Affiliations

  1. Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

    Theo Mantamadiotis, Thomas Lemberger, Susanne C. Bleckmann, Heidrun Kern, Oliver Kretz, Ana Martin Villalba, François Tronche, Christoph Kellendonk, Daniel Gau, Christiane Otto, Wolfgang Schmid & Günther Schütz

  2. Institute of Anatomy, University of Basel, Switzerland

    Josef Kapfhammer

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Correspondence to Günther Schütz.

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Mantamadiotis, T., Lemberger, T., Bleckmann, S. et al. Disruption of CREB function in brain leads to neurodegeneration. Nat Genet 31, 47–54 (2002). https://doi.org/10.1038/ng882

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