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RESEARCH ARTICLE
New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes
Sabiha Abekhoukh, H. Bahar Sahin, Mauro Grossi, Samantha Zongaro, Thomas Maurin, Irene Madrigal, Daniele Kazue-Sugioka, Annick Raas-Rothschild, Mohamed Doulazmi, Pilar Carrera, Andrea Stachon, Steven Scherer, Maria Rita Drula Do Nascimento, Alain Trembleau, Ignacio Arroyo, Peter Szatmari, Isabel M. Smith, Montserrat Milà, Adam C. Smith, Angela Giangrande, Isabelle Caillé, Barbara Bardoni
Disease Models & Mechanisms 2017 10: 463-474; doi: 10.1242/dmm.025809
Sabiha Abekhoukh
1Université Côte d'Azur, Nice, France
2CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne, France
3CNRS Associated International Laboratory (LIA) ‘Neogenex’, 06560 Valbonne, France
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H. Bahar Sahin
4Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France
5CNRS, UMR7104, 67400 Illkirch, France
6Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France
7Université de Strasbourg, 67404 Illkirch, France
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Mauro Grossi
1Université Côte d'Azur, Nice, France
2CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne, France
3CNRS Associated International Laboratory (LIA) ‘Neogenex’, 06560 Valbonne, France
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Samantha Zongaro
1Université Côte d'Azur, Nice, France
2CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne, France
3CNRS Associated International Laboratory (LIA) ‘Neogenex’, 06560 Valbonne, France
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Thomas Maurin
1Université Côte d'Azur, Nice, France
2CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne, France
3CNRS Associated International Laboratory (LIA) ‘Neogenex’, 06560 Valbonne, France
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Irene Madrigal
8Biochemistry and Molecular Genetics Department, Hospital Clinic, 08036 Barcelona, Spain
9Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain
10IDIBAPS, Barcelona, Spain
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Daniele Kazue-Sugioka
1Université Côte d'Azur, Nice, France
2CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne, France
3CNRS Associated International Laboratory (LIA) ‘Neogenex’, 06560 Valbonne, France
11Instituto de Pesquisa Pelé Pequeno Principe, Curitiba 80250-060, Brazil
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Annick Raas-Rothschild
12Institute of Rare Diseases, Institute of Medical Genetics, The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
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Mohamed Doulazmi
13Sorbonne Universités, Université Pierre et Marie Curie, Univ Paris 06, CNRS UMR8256, IBPS, Neuroscience Paris Seine, France
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Pilar Carrera
4Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France
5CNRS, UMR7104, 67400 Illkirch, France
6Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France
7Université de Strasbourg, 67404 Illkirch, France
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Andrea Stachon
11Instituto de Pesquisa Pelé Pequeno Principe, Curitiba 80250-060, Brazil
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Steven Scherer
14Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8
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Maria Rita Drula Do Nascimento
11Instituto de Pesquisa Pelé Pequeno Principe, Curitiba 80250-060, Brazil
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Alain Trembleau
13Sorbonne Universités, Université Pierre et Marie Curie, Univ Paris 06, CNRS UMR8256, IBPS, Neuroscience Paris Seine, France
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Ignacio Arroyo
9Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain
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Peter Szatmari
15Centre for Addiction and Mental Health, Hospital for Sick Children, Department of Psychiatry, University of Toronto, Canada, M5G 1X8
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Isabel M. Smith
16Departments of Pediatrics and Psychology & Neuroscience, Dalhousie University and IWK Health Centre, Halifax, Canada, B3K 6R8
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Montserrat Milà
8Biochemistry and Molecular Genetics Department, Hospital Clinic, 08036 Barcelona, Spain
9Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain
10IDIBAPS, Barcelona, Spain
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Adam C. Smith
11Instituto de Pesquisa Pelé Pequeno Principe, Curitiba 80250-060, Brazil
17Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto and Program in Laboratory Medicine, University Health Network, Toronto, Canada
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Angela Giangrande
4Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France
5CNRS, UMR7104, 67400 Illkirch, France
6Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France
7Université de Strasbourg, 67404 Illkirch, France
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Isabelle Caillé
13Sorbonne Universités, Université Pierre et Marie Curie, Univ Paris 06, CNRS UMR8256, IBPS, Neuroscience Paris Seine, France
18Sorbonne Paris Cité, Université Paris Diderot-Paris 7, 75013 Paris, France
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Barbara Bardoni
1Université Côte d'Azur, Nice, France
2CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne, France
3CNRS Associated International Laboratory (LIA) ‘Neogenex’, 06560 Valbonne, France
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  • For correspondence: bardoni@ipmc.cnrs.fr
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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
http://creativecommons.org/licenses/by/3.0

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • Fragile X
  • Intellectual disability
  • Autism
  • CYFIP1
  • BP1-BP2 deletion

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RESEARCH ARTICLE
New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes
Sabiha Abekhoukh, H. Bahar Sahin, Mauro Grossi, Samantha Zongaro, Thomas Maurin, Irene Madrigal, Daniele Kazue-Sugioka, Annick Raas-Rothschild, Mohamed Doulazmi, Pilar Carrera, Andrea Stachon, Steven Scherer, Maria Rita Drula Do Nascimento, Alain Trembleau, Ignacio Arroyo, Peter Szatmari, Isabel M. Smith, Montserrat Milà, Adam C. Smith, Angela Giangrande, Isabelle Caillé, Barbara Bardoni
Disease Models & Mechanisms 2017 10: 463-474; doi: 10.1242/dmm.025809
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RESEARCH ARTICLE
New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes
Sabiha Abekhoukh, H. Bahar Sahin, Mauro Grossi, Samantha Zongaro, Thomas Maurin, Irene Madrigal, Daniele Kazue-Sugioka, Annick Raas-Rothschild, Mohamed Doulazmi, Pilar Carrera, Andrea Stachon, Steven Scherer, Maria Rita Drula Do Nascimento, Alain Trembleau, Ignacio Arroyo, Peter Szatmari, Isabel M. Smith, Montserrat Milà, Adam C. Smith, Angela Giangrande, Isabelle Caillé, Barbara Bardoni
Disease Models & Mechanisms 2017 10: 463-474; doi: 10.1242/dmm.025809

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