eLife | |
FMRP regulates mRNAs encoding distinct functions in the cell body and dendrites of CA1 pyramidal neurons | |
Katarzyna Cialowicz1  Thomas S Carroll2  Caryn R Hale3  Kevin Mora3  John J Fak3  Jin Joo Kang3  Paula Cutrim3  Kirsty Sawicka3  Robert B Darnell4  | |
[1] Bio-Imaging Resource Center, The Rockefeller University, New York, United States;Bioinformatics Resource Center, The Rockefeller University, New York, United States;Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States;Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, United States;Howard Hughes Medical Institute, Rockefeller University, New York, United States; | |
关键词: local translation; FMRP; RNA-binding proteins; synaptic plasticity; mRNA localization; Mouse; | |
DOI : 10.7554/eLife.71892 | |
来源: eLife Sciences Publications, Ltd | |
【 摘 要 】
Neurons rely on translation of synaptic mRNAs in order to generate activity-dependent changes in plasticity. Here, we develop a strategy combining compartment-specific crosslinking immunoprecipitation (CLIP) and translating ribosome affinity purification (TRAP) in conditionally tagged mice to precisely define the ribosome-bound dendritic transcriptome of CA1 pyramidal neurons. We identify CA1 dendritic transcripts with differentially localized mRNA isoforms generated by alternative polyadenylation and alternative splicing, including many that have altered protein-coding capacity. Among dendritic mRNAs, FMRP targets were found to be overrepresented. Cell-type-specific FMRP-CLIP and TRAP in microdissected CA1 neuropil revealed 383 dendritic FMRP targets and suggests that FMRP differentially regulates functionally distinct modules in CA1 dendrites and cell bodies. FMRP regulates ~15–20% of mRNAs encoding synaptic functions and 10% of chromatin modulators, in the dendrite and cell body, respectively. In the absence of FMRP, dendritic FMRP targets had increased ribosome association, consistent with a function for FMRP in synaptic translational repression. Conversely, downregulation of FMRP targets involved in chromatin regulation in cell bodies suggests a role for FMRP in stabilizing mRNAs containing stalled ribosomes in this compartment. Together, the data support a model in which FMRP regulates the translation and expression of synaptic and nuclear proteins within different compartments of a single neuronal cell type.
【 授权许可】
CC BY
【 预 览 】
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