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. 2013 Sep 18;79(6):1169–1182. doi: 10.1016/j.neuron.2013.06.039

Figure 6.

Figure 6

The CYFIP1 Interactome in Mouse Cortex and Synapses and Its Relevance for Neuropsychiatric Disorders

(A) CYFIP1 interactome, as revealed by MS of the proteins coimmunoprecipitating with CYFIP1 in cortical whole-cell lysate. IP with rabbit IgGs was used as a negative control; n = 3. The identified proteins are listed in Table S2, Table S3.

(B) Validation of CYFIP1 interactors by reverse IP. Lane 1, input (1/100); lanes 2–6, specific IPs; lanes 7–8, controls with rabbit and mouse IgGs. See also Figure S6.

(C) CYFIP1 interactome is partially RNase sensitive. Lane 1, input (1/50); lane 2, CYFIP1 IP; lane 3, CYFIP1 IP after RNase treatment; lane 4, control IP (rabbit IgGs); n = 5.

(D) Outcome of MS analysis of the proteins coimmunoprecipitating with CYFIP1 in cortical synaptoneurosomes. IPs with rabbit IgGs were used as negative control; n = 6. The identified proteins are listed in Table S4.

(E) Many CYFIP1 interactors are linked to neurological diseases. Indicated are the percentages of genes related to intellectual disability (ID), autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), major depressive disorder (MDD), and Alzheimer’s disease (AD) (the diagram is approximate, as some genes are related to more than one disease; see also Table S5).

(F) Proposed model for the interplay of CYFIP1 complexes in brain. In neurons, CYFIP1 is associated with two distinct protein complexes, the CYFIP1-FMRP-eIF4E, which represses translation of specific mRNAs such as Arc/Arg3.1 mRNA, and the WRC (CYFIP1-NCKAP1-WAVE1-ABI2-HSPC300), which regulates actin remodeling. BDNF signaling activates Rac1, and GTP-Rac1 changes the equilibrium between the two CYFIP1 complexes by inducing a conformational change that releases CYFIP1 from eIF4E and relocates it to active WRC. As a consequence, actin cytoskeleton is remodeled and, concomitantly, the translation of proteins that encode cytoskeleton elements and synaptic function and plasticity is activated. The two processes converge to regulate proper spine morphology, which is compromised by perturbations of CYFIP1 expression or interference with CYFIP1-eIF4E and CYFIP1-WRC.