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 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.
VIB Center for Biology of Disease, KULeuven, 3000 Leuven, Belgium; Center for Human Genetics and Leuven Institute for Neuroscience and Disease (LIND), KULeuven, 3000 Leuven, Belgium.
Silvia
S
De Rubeis
Emanuela
E
Pasciuto
Ka Wan
KW
Li
Esperanza
E
Fernández
Daniele
D
Di Marino
Andrea
A
Buzzi
Linnaea E
LE
Ostroff
Eric
E
Klann
Fried J T
FJ
Zwartkruis
Noboru H
NH
Komiyama
Seth G N
SG
Grant
Christel
C
Poujol
Daniel
D
Choquet
Tilmann
T
Achsel
Danielle
D
Posthuma
August B
AB
Smit
Claudia
C
Bagni
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000367:Age Factors; D000634:Aminoquinolines / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002853:Chromatography, Liquid; D004268:DNA-Binding Proteins / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000235:genetics* / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D026121:Indole Alkaloids / Q000494:pharmacology; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D001523:Mental Disorders / Q000235:genetics; D015201:Meta-Analysis as Topic; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D000634:Aminoquinolines; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D051860:Fragile X Messenger Ribonucleoprotein 1; D049452:Green Fluorescent Proteins; D026121:Indole Alkaloids; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D011743:Pyrimidines; D012333:RNA, Messenger; D014157:Transcription Factors; C115472:Cyfip1 protein, mouse; C491779:Elf4 protein, mouse; C497684:Fmr1 protein, mouse; C484362:NCKAP1 protein, human; C487513:NSC 23766; C485184:enhanced green fluorescent protein; C049985:staurosporine aglycone