New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes.
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 itsDrosophilahomolog, dCYFIP. CYFIP1 interacts with the Fragile X mental retardation protein (FMRP, encoded by theFMR1gene), 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 ofCYFIP1and 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.
Université Côte d'Azur, Nice, France.|CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne, France.|CNRS Associated International Laboratory (LIA) 'Neogenex', 06560 Valbonne, France.
Sabiha
0000-0002-8654-2307
S
Abekhoukh
Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France.|CNRS, UMR7104, 67400 Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France.|Université de Strasbourg, 67404 Illkirch, France.
H Bahar
0000-0002-5221-7637
HB
Sahin
Université Côte d'Azur, Nice, France.|CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne, France.|CNRS Associated International Laboratory (LIA) 'Neogenex', 06560 Valbonne, France.
Mauro
0000-0002-2359-7925
M
Grossi
Université Côte d'Azur, Nice, France.|CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne, France.|CNRS Associated International Laboratory (LIA) 'Neogenex', 06560 Valbonne, France.
Samantha
S
Zongaro
Université Côte d'Azur, Nice, France.|CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne, France.|CNRS Associated International Laboratory (LIA) 'Neogenex', 06560 Valbonne, France.
Thomas
0000-0002-8467-3135
T
Maurin
Biochemistry and Molecular Genetics Department, Hospital Clinic, 08036 Barcelona, Spain.|Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain.|IDIBAPS, Barcelona, Spain.
Irene
0000-0003-1857-4902
I
Madrigal
Université Côte d'Azur, Nice, France.|CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne, France.|CNRS Associated International Laboratory (LIA) 'Neogenex', 06560 Valbonne, France.|Instituto de Pesquisa Pelé Pequeno Principe, Curitiba 80250-060, Brazil.
Daniele
D
Kazue-Sugioka
Institute of Rare Diseases, Institute of Medical Genetics, The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.
Annick
A
Raas-Rothschild
Sorbonne Universités, Université Pierre et Marie Curie, Univ Paris 06, CNRS UMR8256, IBPS, Neuroscience Paris Seine, France.
Mohamed
M
Doulazmi
Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France.|CNRS, UMR7104, 67400 Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France.|Université de Strasbourg, 67404 Illkirch, France.
Pilar
0000-0002-3940-9028
P
Carrera
Instituto de Pesquisa Pelé Pequeno Principe, Curitiba 80250-060, Brazil.
Andrea
A
Stachon
Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8.
Steven
S
Scherer
Instituto de Pesquisa Pelé Pequeno Principe, Curitiba 80250-060, Brazil.
Maria Rita
MR
Drula Do Nascimento
Sorbonne Universités, Université Pierre et Marie Curie, Univ Paris 06, CNRS UMR8256, IBPS, Neuroscience Paris Seine, France.
Alain
A
Trembleau
Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain.
Ignacio
I
Arroyo
Centre for Addiction and Mental Health, Hospital for Sick Children, Department of Psychiatry, University of Toronto, Canada, M5G 1X8.
Peter
P
Szatmari
Departments of Pediatrics and Psychology & Neuroscience, Dalhousie University and IWK Health Centre, Halifax, Canada, B3K 6R8.
Isabel M
0000-0001-5525-2123
IM
Smith
Biochemistry and Molecular Genetics Department, Hospital Clinic, 08036 Barcelona, Spain.|Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain.|IDIBAPS, Barcelona, Spain.
Montserrat
M
Milà
Instituto de Pesquisa Pelé Pequeno Principe, Curitiba 80250-060, Brazil.|Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto and Program in Laboratory Medicine, University Health Network, Toronto, Canada.
Adam C
AC
Smith
Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France.|CNRS, UMR7104, 67400 Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France.|Université de Strasbourg, 67404 Illkirch, France.
Angela
A
Giangrande
Sorbonne Universités, Université Pierre et Marie Curie, Univ Paris 06, CNRS UMR8256, IBPS, Neuroscience Paris Seine, France.|Sorbonne Paris Cité, Université Paris Diderot-Paris 7, 75013 Paris, France.
Isabelle
I
Caillé
Université Côte d'Azur, Nice, France bardoni@ipmc.cnrs.fr.|CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne, France.|CNRS Associated International Laboratory (LIA) 'Neogenex', 06560 Valbonne, France.
Barbara
0000-0001-6411-1517
B
Bardoni
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D004843:Epistasis, Genetic; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism*; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D006801:Humans; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009830:Olfactory Bulb / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D051300:Wiskott-Aldrich Syndrome Protein Family; C115472:Cyfip1 protein, mouse; C484666:Sra-1 protein, Drosophila
Autism; BP1-BP2 deletion; CYFIP1; Fragile X; Intellectual disability