title: A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis.
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 alpha(13) subunits of G proteins (Galpha(13)). RNA-interference-mediated knockdown of APT1 and the expression of membrane-localized Galpha(13) both suppress spine enlargement caused by inhibition of miR-138, suggesting that APT1-regulated depalmitoylation of Galpha(13) 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.
authors.affiliation: Interdisziplinäres Zentrum für Neurowissenschaften, SFB488 Junior Group, Universität Heidelberg, and Institut für Neuroanatomie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siegel
authors.forename: Gregor
authors.initials: G
authors.lastname: Obernosterer
authors.forename: Roberto
authors.initials: R
authors.lastname: Fiore
authors.forename: Martin
authors.initials: M
authors.lastname: Oehmen
authors.forename: Silvia
authors.initials: S
authors.lastname: Bicker
authors.forename: Mette
authors.initials: M
authors.lastname: Christensen
authors.forename: Sharof
authors.initials: S
authors.lastname: Khudayberdiev
authors.forename: Philipp F
authors.initials: PF
authors.lastname: Leuschner
authors.forename: Clara J L
authors.initials: CJ
authors.lastname: Busch
authors.forename: Christina
authors.initials: C
authors.lastname: Kane
authors.forename: Katja
authors.initials: K
authors.lastname: Hübel
authors.forename: Frank
authors.initials: F
authors.lastname: Dekker
authors.forename: Christian
authors.initials: C
authors.lastname: Hedberg
authors.forename: Balamurugan
authors.initials: B
authors.lastname: Rengarajan
authors.forename: Carsten
authors.initials: C
authors.lastname: Drepper
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
authors.forename: Sakari
authors.initials: S
authors.lastname: Kauppinen
authors.forename: Michael E
authors.initials: ME
authors.lastname: Greenberg
authors.forename: Andreas
authors.initials: A
authors.lastname: Draguhn
authors.forename: Marc
authors.initials: M
authors.lastname: Rehmsmeier
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez
authors.forename: Gerhard M
authors.initials: GM
authors.lastname: Schratt
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D049229:Dendritic Spines / Q000201:enzymology / Q000648:ultrastructure; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D054878:Lipoylation; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009024:Morphogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D017470:Receptors, Glutamate; C402226:LYPLA1 protein, human; D013869:Thiolester Hydrolases; D044365:GTP-Binding Protein alpha Subunits, G12-G13