A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome

Dev Cell. 2008 Jun;14(6):926-39. doi: 10.1016/j.devcel.2008.04.003.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Dendrites / drug effects
  • Dendrites / metabolism*
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / chemistry
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism*
  • Fragile X Syndrome / genetics*
  • Fragile X Syndrome / metabolism
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / cytology
  • In Situ Hybridization, Fluorescence
  • Kinesin / antagonists & inhibitors
  • Mice
  • Mice, Knockout
  • Microscopy, Video
  • Models, Biological
  • Protein Structure, Tertiary
  • Pseudopodia / metabolism*
  • Pseudopodia / pathology
  • RNA Transport*
  • RNA, Messenger / metabolism*
  • Sulfuric Acid Esters / pharmacology

Substances

  • RNA, Messenger
  • Sulfuric Acid Esters
  • adociasulfate-2
  • Fragile X Mental Retardation Protein
  • Green Fluorescent Proteins
  • Kinesin