CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation

The CYFIP1/SRA1 gene is located in a chromosomal region linked to various neurological disorders, including intellectual disability, autism, and schizophrenia. CYFIP1 plays a dual role in two apparently unrelated processes, inhibiting local protein synthesis and favoring actin remodeling. Here, we s...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2013-09, Vol.79 (6), p.1169-1182
Main Authors: De Rubeis, Silvia, Pasciuto, Emanuela, Li, Ka Wan, Fernández, Esperanza, Di Marino, Daniele, Buzzi, Andrea, Ostroff, Linnaea E., Klann, Eric, Zwartkruis, Fried J.T., Komiyama, Noboru H., Grant, Seth G.N., Poujol, Christel, Choquet, Daniel, Achsel, Tilmann, Posthuma, Danielle, Smit, August B., Bagni, Claudia
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - chemistry
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Age Factors
Aminoquinolines - pharmacology
Analysis of Variance
Animals
Brain-derived neurotrophic factor
Brain-Derived Neurotrophic Factor - pharmacology
Carbazoles - pharmacology
Cells, Cultured
Cerebral Cortex - cytology
Chromatography, Liquid
Crystal structure
Dendritic Spines - drug effects
Dendritic Spines - genetics
Dendritic Spines - ultrastructure
DNA-Binding Proteins - metabolism
Enzyme Inhibitors - pharmacology
Fragile X Mental Retardation Protein - genetics
Fragile X Mental Retardation Protein - metabolism
Fragile X Mental Retardation Protein - ultrastructure
Gene Expression Regulation - genetics
Green Fluorescent Proteins - genetics
Green Fluorescent Proteins - metabolism
Humans
Immunoprecipitation
In Vitro Techniques
Indole Alkaloids - pharmacology
Luminescent Proteins - metabolism
Male
Mental Disorders - genetics
Meta-Analysis as Topic
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microscopy, Immunoelectron
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Nerve Tissue Proteins - ultrastructure
Neurons
Neurons - drug effects
Neurons - ultrastructure
Protein Biosynthesis - drug effects
Protein Biosynthesis - genetics
Protein synthesis
Proteins
Pyrimidines - pharmacology
RNA, Messenger - metabolism
Schizophrenia
Synaptosomes - drug effects
Synaptosomes - metabolism
Synaptosomes - ultrastructure
Tandem Mass Spectrometry
Time Factors
Transcription Factors - metabolism
Transfection
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Summary:The CYFIP1/SRA1 gene is located in a chromosomal region linked to various neurological disorders, including intellectual disability, autism, and schizophrenia. CYFIP1 plays a dual role in two apparently unrelated processes, inhibiting local protein synthesis and favoring actin remodeling. Here, we show that brain-derived neurotrophic factor (BDNF)-driven synaptic signaling releases CYFIP1 from the translational inhibitory complex, triggering translation of target mRNAs and shifting CYFIP1 into the WAVE regulatory complex. Active Rac1 alters the CYFIP1 conformation, as demonstrated by intramolecular FRET, and is key in changing the equilibrium of the two complexes. CYFIP1 thus orchestrates the two molecular cascades, protein translation and actin polymerization, each of which is necessary for correct spine morphology in neurons. The CYFIP1 interactome reveals many interactors associated with brain disorders, opening new perspectives to define regulatory pathways shared by neurological disabilities characterized by spine dysmorphogenesis. •BDNF-Rac1 signaling redistributes CYFIP1 between eIF4E and WRC•FRET demonstrates that BDNF-Rac1 signaling alters CYFIP1 conformation•CYFIP1-eIF4E-WRC regulates ARC synthesis, actin polymerization, and spine morphology•The CYFIP1 interactome is enriched in genes implicated in neurological disorders CYFIP1 plays a dual role in inhibiting local protein synthesis and favoring actin remodeling. De Rubeis et al. show that BDNF-driven synaptic signaling releases CYFIP1 from the translational inhibitory complex, triggering translation of target mRNAs and shifting CYFIP1 into the WAVE regulatory complex.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2013.06.039