New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes

Disease Models & Mechanisms

Montserrat Mil๠ Irene Madrigal¹  Ignacio Arroyo²  Peter Szatmari³  Isabel M. Smith⁴  Steven Scherer⁵  Angela Giangrande⁶  H. Bahar Sahin⁶  Pilar Carrera⁶  Annick Raas-Rothschild⁷  Adam C. Smith⁸  Andrea Stachon⁸  Maria Rita Drula Do Nascimento⁸  Alain Trembleau⁹  Mohamed Doulazmi⁹  Isabelle Caillé⁹  Barbara Bardoni^1,10  Mauro Grossi^1,10  Samantha Zongaro^1,10  Sabiha Abekhoukh^1,10  Thomas Maurin^1,10  Daniele Kazue-Sugioka^1,10 

[1] Biochemistry and Molecular Genetics Department, Hospital Clinic, 08036 Barcelona, Spain;Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain;Centre for Addiction and Mental Health, Hospital for Sick Children, Department of Psychiatry, University of Toronto, Canada, M5G 1X8;Departments of Pediatrics and Psychology & Neuroscience, Dalhousie University and IWK Health Centre, Halifax, Canada, B3K 6R8;Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8;Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France;Institute of Rare Diseases, Institute of Medical Genetics, The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel;Instituto de Pesquisa Pelé Pequeno Principe, Curitiba 80250-060, Brazil;Sorbonne Universités, Université Pierre et Marie Curie, Univ Paris 06, CNRS UMR8256, IBPS, Neuroscience Paris Seine, France;Université Côte d'Azur, Nice, France;

关键词: Fragile X;    Intellectual disability;    Autism;    CYFIP1;    BP1-BP2 deletion;   

DOI  :  10.1242/dmm.025809

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown