New Insights Into the Regulatory Function of Cyfip1 in the Context of Wave- and Fmrp-Containing Complexes

Abstract

Cytoplasmic 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 theWAVE 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.