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. https://resolver.caltech.edu/CaltechAUTHORS:20120321-083513932
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Abstract
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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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. | |||||||||||||||
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Issue or Number: | 3 | |||||||||||||||
PubMed Central ID: | PMC3288555 | |||||||||||||||
DOI: | 10.1038/NCHEMBIO.770 | |||||||||||||||
Record Number: | CaltechAUTHORS:20120321-083513932 | |||||||||||||||
Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20120321-083513932 | |||||||||||||||
Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | |||||||||||||||
ID Code: | 29788 | |||||||||||||||
Collection: | CaltechAUTHORS | |||||||||||||||
Deposited By: | Tony Diaz | |||||||||||||||
Deposited On: | 21 Mar 2012 20:21 | |||||||||||||||
Last Modified: | 09 Nov 2021 19:29 |
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