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Dynamic O-GlcNAc modification regulates CREB-mediated gene expression and memory formation

Rexach, Jessica E. and Clark, Peter M. and Mason, Daniel E. and Neve, Rachael L. and Peters, Eric C. and Hsieh-Wilson, Linda C. (2012) Dynamic O-GlcNAc modification regulates CREB-mediated gene expression and memory formation. Nature Chemical Biology, 8 (3). pp. 253-261. ISSN 1552-4450. PMCID PMC3288555. doi:10.1038/NCHEMBIO.770.

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The transcription factor cyclic AMP–response element binding protein (CREB) is a key regulator of many neuronal processes, including brain development, circadian rhythm and long-term memory. Studies of CREB have focused on its phosphorylation, although the diversity of CREB functions in the brain suggests additional forms of regulation. Here we expand on a chemoenzymatic strategy for quantifying glycosylation stoichiometries to characterize the functional roles of CREB glycosylation in neurons. We show that CREB is dynamically modified with an O-linked β-N-acetyl-D-glucosamine sugar in response to neuronal activity and that glycosylation represses CREB-dependent transcription by impairing its association with CREB-regulated transcription coactivator (CRTC; also known as transducer of regulated CREB activity). Blocking glycosylation of CREB alters cellular function and behavioral plasticity, enhancing both axonal and dendritic growth and long-term memory consolidation. Our findings demonstrate a new role for O-glycosylation in memory formation and provide a mechanistic understanding of how glycosylation contributes to critical neuronal functions. Moreover, we identify a previously unknown mechanism for the regulation of activity-dependent gene expression, neural development and memory.

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Hsieh-Wilson, Linda C.0000-0001-5661-1714
Additional Information:© 2011 Nature Publishing Group. Received 24 May 2011; Accepted 17 October 2011; Published online 22 January 2012. We thank M. Antoniou (King’s College London School of Medicine) for the pA2UCOE-EGFP construct, M. Greenberg (Harvard University) for the pLEMPRA-GOI and pLLX-shRNA constructs, G. Hart (The John Hopkins University School of Medicine) for the OGT-specific antibody, S. Josselyn (University of Toronto) for the p1005-CREB construct, R. Lansford (California Institute of Technology) for the pLenti PGK-H2B-mCherry construct, R. Malenka (Stanford University) and X. Yu (Shanghai Institutes for Biological Sciences) for the pcDNA3-Dkk-1-Flag and Ncad(intra) constructs, P. Qasba (US National Cancer Institute) for the Y289L GalT construct and L. Wells (University of Georgia) for the pDEST-HA-OGA construct. We thank S.-H. Yu (California Institute of Technology) for synthesizing the UDP-ketogalactose substrate and D. Anderson (California Institute of Technology) for providing the fear conditioning apparatus. We thank A. Silva for a critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health (R01 GM084724 to L.C.H.-W., F31 NS056525 to J.E.R. and National Research Service Award Training Grant 5T32 GM07737 to P.M.C.). Author contributions: L.C.H.-W. designed, directed and coordinated the project. P.M.C. and J.E.R. designed and performed the experiments except where otherwise noted. D.E.M. and E.C.P. performed the MS analyses; R.L.N. prepared the HSV. P.M.C., J.E.R. and L.C.H.-W. wrote the manuscript, and all authors participated in editing it.
Funding AgencyGrant Number
NIHR01 GM084724
NIH Postdoctoral FellowshipF31 NS056525
NIH Predoctoral Fellowship5T32 GM07737
Issue or Number:3
PubMed Central ID:PMC3288555
Record Number:CaltechAUTHORS:20120321-083513932
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:29788
Deposited By: Tony Diaz
Deposited On:21 Mar 2012 20:21
Last Modified:09 Nov 2021 19:29

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