Mef2-mediated transcription of the miR379-410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels.
Neuronal activity orchestrates the proper development of the neuronal circuitry by regulating both transcriptional and post-transcriptional gene expression programmes. How these programmes are coordinated, however, is largely unknown. We found that the transcription of miR379-410, a large cluster of brain-specific microRNAs (miRNAs), is induced by increasing neuronal activity in primary rat neurons. Results from chromatin immunoprecipitation and luciferase reporter assays suggest that binding of the transcription factor myocyte enhancing factor 2 (Mef2) upstream of miR379-410 is necessary and sufficient for activity-dependent transcription of the cluster. Mef2-induced expression of at least three individual miRNAs of the miR379-410 cluster is required for activity-dependent dendritic outgrowth of hippocampal neurons. One of these miRNAs, the dendritic miR-134, promotes outgrowth by inhibiting translation of the mRNA encoding for the translational repressor Pumilio2. In summary, we have described a novel regulatory pathway that couples activity-dependent transcription to miRNA-dependent translational control of gene expression during neuronal development.
Fiore
Roberto
R
Interdisziplinäres Zentrum für Neurowissenschaften, SFB488 Junior Group, Universität Heidelberg, and Institut für Neuroanatomie, Universitätsklinikum Heidelberg, Heidelberg, Germany.
Khudayberdiev
Sharof
S
Christensen
Mette
M
Siegel
Gabriele
G
Flavell
Steven W
SW
Kim
Tae-Kyung
TK
Greenberg
Michael E
ME
Schratt
Gerhard
G
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D003712:Dendrites / Q000378:metabolism*; D015536:Down-Regulation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D026161:MADS Domain Proteins / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D005810:Multigene Family; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D038081:Organogenesis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic
D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578037:MEF2A protein, rat; D035683:MicroRNAs; D018006:Myogenic Regulatory Factors; C539713:PUM2 protein, rat; D016601:RNA-Binding Proteins