A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome.
The function of local protein synthesis in synaptic plasticity and its dysregulation in fragile X syndrome (FXS) is well studied, however the contribution of regulated mRNA transport to this function remains unclear. We report a function for the fragile X mental retardation protein (FMRP) in the rapid, activity-regulated transport of mRNAs important for synaptogenesis and plasticity. mRNAs were deficient in glutamatergic signaling-induced dendritic localization in neurons from Fmr1 KO mice, and single mRNA particle dynamics in live neurons revealed diminished kinesis. Motor-dependent translocation of FMRP and cognate mRNAs involved the C terminus of FMRP and kinesin light chain, and KO brain showed reduced kinesin-associated mRNAs. Acute suppression of FMRP and target mRNA transport in WT neurons resulted in altered filopodia-spine morphology that mimicked the FXS phenotype. These findings highlight a mechanism for stimulus-induced dendritic mRNA transport and link its impairment in a mouse model of FXS to altered developmental morphologic plasticity.
Dictenberg
Jason B
JB
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Dictenberg@genectr.hunter.cuny.edu
Swanger
Sharon A
SA
Antar
Laura N
LN
Singer
Robert H
RH
Bassell
Gary J
GJ
D000818:Animals; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D017404:In Situ Hybridization, Fluorescence; D016547:Kinesins / Q000037:antagonists & inhibitors; D051379:Mice; D018345:Mice, Knockout; D018715:Microscopy, Video; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D011554:Pseudopodia / Q000378:metabolism* / Q000473:pathology; D034443:RNA Transport; D012333:RNA, Messenger / Q000378:metabolism*; D013463:Sulfuric Acid Esters / Q000494:pharmacology
D051860:Fragile X Messenger Ribonucleoprotein 1; D049452:Green Fluorescent Proteins; D016547:Kinesins; D012333:RNA, Messenger; D013463:Sulfuric Acid Esters; C111568:adociasulfate-2