Article abstract
Nature Cell Biology 11, 705 - 716 (2009)
Published online: 24 May 2009 | doi:10.1038/ncb1876
A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis
Gabriele Siegel1,11, Gregor Obernosterer1,11, Roberto Fiore1, Martin Oehmen3, Silvia Bicker1, Mette Christensen1,4, Sharof Khudayberdiev1, Philipp F. Leuschner2, Clara J. L. Busch2, Christina Kane5, Katja Hübel6, Frank Dekker6, Christian Hedberg9, Balamurugan Rengarajan6, Carsten Drepper7,10, Herbert Waldmann6, Sakari Kauppinen4,8, Michael E. Greenberg5, Andreas Draguhn3, Marc Rehmsmeier7,10, Javier Martinez2 & Gerhard M. Schratt1
Abstract
The microRNA pathway has been implicated in the regulation of synaptic protein synthesis and ultimately in dendritic spine morphogenesis, a phenomenon associated with long-lasting forms of memory. However, the particular microRNAs (miRNAs) involved are largely unknown. Here we identify specific miRNAs that function at synapses to control dendritic spine structure by performing a functional screen. One of the identified miRNAs, miR-138, is highly enriched in the brain, localized within dendrites and negatively regulates the size of dendritic spines in rat hippocampal neurons. miR-138 controls the expression of acyl protein thioesterase 1 (APT1), an enzyme regulating the palmitoylation status of proteins that are known to function at the synapse, including the 
13 subunits of G proteins (G13). RNA-interference-mediated knockdown of APT1 and the expression of membrane-localized G13 both suppress spine enlargement caused by inhibition of miR-138, suggesting that APT1-regulated depalmitoylation of G13 might be an important downstream event of miR-138 function. Our results uncover a previously unknown miRNA-dependent mechanism in neurons and demonstrate a previously unrecognized complexity of miRNA-dependent control of dendritic spine morphogenesis.
- Interdisziplinäres Zentrum für Neurowissenschaften, SFB488 Junior Group, Universität Heidelberg, and Institut für Neuroanatomie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
- Institute of Molecular Biotechnology, IMBA, Austrian Academy of Sciences, Dr. Bohr Gasse 3, 1030 Vienna, Austria.
- Institut für Physiologie und Pathophysiologie, Universität Heidelberg, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany.
- Wilhelm Johannsen Center for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, DK-2200 Cph N, Denmark.
- Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA.
- Max-Planck-Institut für molekulare Physiologie, Abteilung Chemische Biologie, and Technische Universität Dortmund, Fakultät Chemie, Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
- Center for Biotechnology (CeBiTec), Universität Bielefeld, 33594 Bielefeld, Germany.
- Santaris Pharma, Boege Alle 3, DK-2970 Hoersholm, Denmark.
- Max Planck Institute of Molecular Physiology, Chemical Biology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
- Present addresses: Institute for Clinical Neurobiology, ZEMM, Zinklesweg 10, Würzburg University, 97078 Würzburg, Germany (C.D.); Gregor Mendel Institute of Molecular Plant Biology, Dr. Bohr-Gasse 3, 1030 Vienna, Austria (M.R.).
- These authors contributed equally to this work.
Correspondence to: Javier Martinez2 e-mail: javier.martinez@imba.oeaw.ac.at
Correspondence to: Gerhard M. Schratt1 e-mail: schratt@ana.uni-heidelberg.de
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