Fragile X syndrome is caused by the absence of the fragile X mental-retardation protein (FMRP), an mRNAbinding protein, which may play important roles in the regulation of dendritic mRNA localization and/or synaptic protein synthesis. We have recently applied highresolution fluorescence imaging methods to document the presence, motility and activity-dependent regulation of FMRP granule trafficking in dendrites and spines of cultured hippocampal neurons. In this study, we show that FMRP granules distribute to F-actin-rich compartments, including filopodia, spines and growth cones during the staged development of hippocampal neurons in culture. Fragile X mental-retardation protein granules were shown to colocalize with ribosomes, ribosomal RNA and MAP1B mRNA, a known FMRP target, which encodes a protein important for microtubule and actin stabilization. The levels of FMRP within dendrites were reduced by disruption of microtubule dynamics, but not by disruption of F-actin. Direct measurements of FMRP transport kinetics using fluorescence recovery after photobleaching in living neurons showed that microtubules were required to induce the mGluR-dependent translocation into dendrites. This study provides further characterization of the composition and regulated trafficking of FMRP granules in dendrites of hippocampal neurons.
Observations that polyribosomes are localized near dendritic spines and beneath synapses has led to a hypothesis of synapse-specific gene expression in which local synthesis would provide a mechanism to influence synaptic structure and strength (l).The active transport of specific mRNAs into dendrites and spines may be a regulated mechanism to target synaptic and regulatory proteins to postsynaptic locations and influence synaptic activity. RNA granules labeled with the vital dye, SYT014, were observed to localize into developing neurites in response to the neurotrophin, NT-3 (2). Neurotrophins have been shown to enhance synaptic activity by a process which requires new protein synthesis (3). The identity and source of newly synthesized proteins which are required to enhance synaptic strength in response to NT-3 are unknown. CaMKIIαRNA localization into dendrites has been shown to occur during long term potentiation (4).
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