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 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.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
S.A., A.G., A.T., I.C., T.M., B.B. designed the experiments. S.A., H.B.S., M.G., S.Z., I.M., D.K.-S., P.C., I.C. performed the experiments. S.A., H.B.S., M.G., S.Z., P.C., M.D., A.T., A.G., I.C., T.M., B.B. analyzed the data. A.S., I.M., A.R.-R., A.S., S.S., M.R.D.D.N., I.A., S.P., I.M.S., M.M., A.C.S. provided some material. S.A., I.C., B.B. wrote the manuscript. All the authors reviewed the manuscript.
Funding
This study was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM); Centre National de la Recherche Scientifique (CNRS); Laboratoire International Associé CNRS ‘NEOGENEX’; Agence Nationale de la Recherche (ANR-11-LABX-0028-01 and ANR-12-SVSE8-0022); Fondation pour la Recherche Médicale (FRM) (DEQ20140329490; ING20140129004); Fondation Jérôme Lejeune; Monaco against Autism Foundation; Science without Borders, CAPES-PVE 88887.064206/2014-00; S.Z. was supported by an AFM-Téléthon fellowship and T.M. by the FRAXA Research Foundation.
Supplementary information
Supplementary information available online at http://dmm.biologists.org/lookup/doi/10.1242/dmm.025809.supplemental
- Received April 3, 2016.
- Accepted February 2, 2017.
- © 2017. Published by The Company of Biologists Ltd
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