Abstract
ABSTRACTCytoplasmic FMRP interacting protein 1 (CYFIP1) is a candidate gene for intellectual disability (ID), autism, schizophrenia and epilepsy. It is a member of a family of proteins that is highly conserved during evolution, sharing high homology with its Drosophila homolog, dCYFIP. CYFIP1 interacts with the Fragile X mental retardation protein (FMRP, encoded by the FMR1 gene), whose absence causes Fragile X syndrome, and with the translation initiation factor eIF4E. It is a member of the WAVE regulatory complex (WRC), thus representing a link between translational regulation and the actin cytoskeleton. Here, we present data showing a correlation between mRNA levels of CYFIP1 and other members of the WRC. This suggests a tight regulation of the levels of the WRC members, not only by post-translational mechanisms, as previously hypothesized. Moreover, we studied the impact of loss of function of both CYFIP1 and FMRP on neuronal growth and differentiation in two animal models – fly and mouse. We show that these two proteins antagonize each other's function not only during neuromuscular junction growth in the fly but also during new neuronal differentiation in the olfactory bulb of adult mice. Mechanistically, FMRP and CYFIP1 modulate mTor signaling in an antagonistic manner, likely via independent pathways, supporting the results obtained in mouse as well as in fly at the morphological level. Collectively, our results illustrate a new model to explain the cellular roles of FMRP and CYFIP1 and the molecular significance of their interaction.
Highlights
IntroductionCytoplasmic FMRP interacting protein 1 (CYFIP1) is a member of the WAVE regulatory complex (WRC) along with CYFIP2, WAVE (WAS protein family member), NAP1 (NCKAP1 or HEM1 in hematopoietic cells), ABI1 (or one of its paralogous proteins, ABI2 or NESH) and HSPC300 ( known as BRK1) (Cory and Ridley, 2002)
Cytoplasmic FMRP interacting protein 1 (CYFIP1) is a member of the WAVE regulatory complex (WRC) along with CYFIP2, WAVE (WAS protein family member), NAP1 (NCKAP1 or HEM1 in hematopoietic cells), ABI1 and HSPC300 (Cory and Ridley, 2002)
In order to dissect the epistatic interaction between these two proteins, we explored the neuromuscular junction (NMJ) phenotype of transheterozygotes expressing just one copy of each gene and we observed that this phenotype is not statistically different from that of each heterozygote (Fig. S1A)
Summary
Cytoplasmic FMRP interacting protein 1 (CYFIP1) is a member of the WAVE regulatory complex (WRC) along with CYFIP2, WAVE (WAS protein family member), NAP1 (NCKAP1 or HEM1 in hematopoietic cells), ABI1 (or one of its paralogous proteins, ABI2 or NESH) and HSPC300 ( known as BRK1) (Cory and Ridley, 2002). The whole complex is per se inactive, but its function is activated by the interaction between CYFIP1/2 and Rac-GTP (Derivery et al, 2009) This interaction determines the scission of the complex into two subcomplexes: one including CYFIP1/2, NCKAP1 and ABI1 and the other one associating WAVE and HSPC. CYFIP1 and CYFIP2 are members of a family of proteins interacting with the Fragile X mental retardation protein (FMRP, encoded by FMR1) in mammals, as well as in the fly (Abekhoukh and Bardoni, 2014; Schenck et al, 2001, 2003). The subcomplex including dCYFIP (the Drosophila ortholog of CYFIP1/ 2, known as Sra-1) and Kette (ortholog of NAP1) has been reported to interact with a plethora of membrane proteins, including protocadherins, Roundabout (Robo) single-pass transmembrane receptors, protocadherins, netrin receptors, neuroligins, G-proteincoupled receptors and ion channels in the fly (Chen et al, 2014; Pham et al, 2016)
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