FMRP regulates mRNAs encoding distinct functions in the cell body and dendrites of CA1 pyramidal neurons

eLife

Katarzyna Cialowicz¹  Thomas S Carroll²  Kirsty Sawicka³  Kevin Mora³  Caryn R Hale³  John J Fak³  Paula Cutrim³  Jin Joo Kang³  Robert B Darnell³ 

[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;

关键词: local translation;    FMRP;    RNA-binding proteins;    synaptic plasticity;    mRNA localization;   

DOI  :  10.7554/eLife.71892

来源: DOAJ

【 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】

Unknown