A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis.
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.
Siegel
Gabriele
G
Interdisziplinäres Zentrum für Neurowissenschaften, SFB488 Junior Group, Universität Heidelberg, and Institut für Neuroanatomie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
Obernosterer
Gregor
G
Fiore
Roberto
R
Oehmen
Martin
M
Bicker
Silvia
S
Christensen
Mette
M
Khudayberdiev
Sharof
S
Leuschner
Philipp F
PF
Busch
Clara J L
CJ
Kane
Christina
C
Hübel
Katja
K
Dekker
Frank
F
Hedberg
Christian
C
Rengarajan
Balamurugan
B
Drepper
Carsten
C
Waldmann
Herbert
H
Kauppinen
Sakari
S
Greenberg
Michael E
ME
Draguhn
Andreas
A
Rehmsmeier
Marc
M
Martinez
Javier
J
Schratt
Gerhard M
GM
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*
D035683:MicroRNAs; D017470:Receptors, Glutamate; C402226:LYPLA1 protein, human; D013869:Thiolester Hydrolases; D044365:GTP-Binding Protein alpha Subunits, G12-G13