The FMRP/GRK4 mRNA interaction uncovers a new mode of binding of the Fragile X mental retardation protein in cerebellum

Thomas Maurin, Mireille Melko, Sabiha Abekhoukh, Olfa Khalfallah, Laetitia Davidovic, Marielle Jarjat, Simona D'Antoni, Maria Vincenza Catania, Hervé Moine, Elias Bechara, Barbara Bardoni

Research output: Contribution to journalArticle

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Abstract

Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is caused by the silencing of the FMR1 gene encoding an RNA-binding protein (FMRP) mainly involved in translational control. We characterized the interaction between FMRP and the mRNA of GRK4, a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase super-family, both in vitro and in vivo. While the mRNA level of GRK4 is unchanged in the absence or in the presence of FMRP in different regions of the brain, GRK4 protein level is increased in Fmr1-null cerebellum, suggesting that FMRP negatively modulates the expression of GRK4 at the translational level in this brain region. The Cterminal region of FMRP interacts with a domain of GRK4 mRNA, that we called G4RIF, that is folded in four stem loops. The SL1 stem loop of G4RIF is protected by FMRP and is part of the S1/S2 subdomain that directs translation repression of a reporter mRNA by FMRP. These data confirm the role of the G4RIF/FMRP complex in translational regulation. Considering the role of GRK4 in GABAB receptors desensitization, our results suggest that an increased GRK4 levels in FXS might contribute to cerebellum-dependent phenotypes through a deregulated desensitization of GABAB receptors.

Original languageEnglish
Pages (from-to)8540-8550
Number of pages11
JournalNucleic Acids Research
Volume43
Issue number17
DOIs
Publication statusPublished - Sep 30 2015

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Fragile X Mental Retardation Protein
Cerebellum
Fragile X Syndrome
Messenger RNA
G-Protein-Coupled Receptor Kinases
RNA-Binding Proteins
Guanine Nucleotides
Brain
Gene Silencing
Intellectual Disability
Carrier Proteins
Phenotype
Proteins

ASJC Scopus subject areas

  • Genetics
  • Medicine(all)

Cite this

Maurin, T., Melko, M., Abekhoukh, S., Khalfallah, O., Davidovic, L., Jarjat, M., ... Bardoni, B. (2015). The FMRP/GRK4 mRNA interaction uncovers a new mode of binding of the Fragile X mental retardation protein in cerebellum. Nucleic Acids Research, 43(17), 8540-8550. https://doi.org/10.1093/nar/gkv801

The FMRP/GRK4 mRNA interaction uncovers a new mode of binding of the Fragile X mental retardation protein in cerebellum. / Maurin, Thomas; Melko, Mireille; Abekhoukh, Sabiha; Khalfallah, Olfa; Davidovic, Laetitia; Jarjat, Marielle; D'Antoni, Simona; Catania, Maria Vincenza; Moine, Hervé; Bechara, Elias; Bardoni, Barbara.

In: Nucleic Acids Research, Vol. 43, No. 17, 30.09.2015, p. 8540-8550.

Research output: Contribution to journalArticle

Maurin, T, Melko, M, Abekhoukh, S, Khalfallah, O, Davidovic, L, Jarjat, M, D'Antoni, S, Catania, MV, Moine, H, Bechara, E & Bardoni, B 2015, 'The FMRP/GRK4 mRNA interaction uncovers a new mode of binding of the Fragile X mental retardation protein in cerebellum', Nucleic Acids Research, vol. 43, no. 17, pp. 8540-8550. https://doi.org/10.1093/nar/gkv801
Maurin, Thomas ; Melko, Mireille ; Abekhoukh, Sabiha ; Khalfallah, Olfa ; Davidovic, Laetitia ; Jarjat, Marielle ; D'Antoni, Simona ; Catania, Maria Vincenza ; Moine, Hervé ; Bechara, Elias ; Bardoni, Barbara. / The FMRP/GRK4 mRNA interaction uncovers a new mode of binding of the Fragile X mental retardation protein in cerebellum. In: Nucleic Acids Research. 2015 ; Vol. 43, No. 17. pp. 8540-8550.
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