Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132.
MicroRNAs (miRNAs) are noncoding RNAs that suppress translation of specific mRNAs. The miRNA machinery interacts with fragile X mental retardation protein (FMRP), which functions as translational repressor. We show that miR-125b and miR-132, as well as several other miRNAs, are associated with FMRP in mouse brain. miR-125b and miR-132 had largely opposing effects on dendritic spine morphology and synaptic physiology in hippocampal neurons. FMRP knockdown ameliorates the effect of miRNA overexpression on spine morphology. We identified NMDA receptor subunit NR2A as a target of miR-125b and show that NR2A mRNA is specifically associated with FMRP in brain. In hippocampal neurons, NR2A expression is negatively regulated through its 3' UTR by FMRP, miR-125b, and Argonaute 1. Regulation of NR2A 3'UTR by FMRP depends in part on miR-125b. Because NMDA receptor subunit composition profoundly affects synaptic plasticity, these observations have implications for the pathophysiology of fragile X syndrome, in which plasticity is altered.
The Picower Institute for Learning and Memory, Departments of Brain and Cognitive Sciences and Biology, Massachusetts Institute of Technology, Cambridge, MA 02319, USA. dieter.edbauer@med.uni-muenchen.de
Dieter
D
Edbauer
Joel R
JR
Neilson
Kelly A
KA
Foster
Chi-Fong
CF
Wang
Daniel P
DP
Seeburg
Matthew N
MN
Batterton
Tomoko
T
Tada
Bridget M
BM
Dolan
Phillip A
PA
Sharp
Morgan
M
Sheng
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism; D004622:Embryo, Mammalian; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D014162:Transfection / Q000379:methods
D039642:Eukaryotic Initiation Factors; D051860:Fragile X Messenger Ribonucleoprotein 1; D049452:Green Fluorescent Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C497684:Fmr1 protein, mouse; C546976:MIRN132 microRNA, mouse; C527468:Mirn125 microRNA, mouse; C120997:NR2A NMDA receptor; C485184:enhanced green fluorescent protein