TY - JOUR
T1 - A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis
AU - Siegel, Gabriele
AU - Obernosterer, Gregor
AU - Fiore, Roberto
AU - Oehmen, Martin
AU - Bicker, Silvia
AU - Christensen, Mette
AU - Khudayberdiev, Sharof
AU - Leuschner, Philipp F
AU - Busch, Clara J L
AU - Kane, Christina
AU - Hübel, Katja
AU - Dekker, Frank
AU - Hedberg, Christian
AU - Rengarajan, Balamurugan
AU - Drepper, Carsten
AU - Waldmann, Herbert
AU - Kauppinen, Sakari
AU - Greenberg, Michael E
AU - Draguhn, Andreas
AU - Rehmsmeier, Marc
AU - Martinez, Javier
AU - Schratt, Gerhard M
N1 - Keywords: Animals; Base Sequence; Cell Line; Dendritic Spines; GTP-Binding Protein alpha Subunits, G12-G13; Gene Expression Profiling; Hippocampus; Humans; Lipoylation; Mice; Mice, Inbred C57BL; MicroRNAs; Molecular Sequence Data; Morphogenesis; Neurons; Oligonucleotide Array Sequence Analysis; Rats; Receptors, Glutamate; Synapses; Thiolester Hydrolases
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
U2 - 10.1038/ncb1876
DO - 10.1038/ncb1876
M3 - Journal article
C2 - 19465924
SN - 1465-7392
VL - 11
SP - 705
EP - 716
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 6
ER -