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Absence of the Fragile X Mental Retardation Protein results in defects of RNA editing of neuronal mRNAs in mouse

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Titel: Absence of the Fragile X Mental Retardation Protein results in defects of RNA editing of neuronal mRNAs in mouse
Autoren: Alice Filippini, Valentina Salvi, Jessica Mingardi, Luca La Via, Laura Sancillo, Claudia Bagni, Caroline Lacoux, Francesca Zalfa, Daniela Bosisio, Maria Zingariello, Laura Pacini, Daniela Bonini, Alessandro Barbon
Weitere Verfasser: ProdInra, Migration, Università degli Studi di Brescia = University of Brescia (UniBs), Department of Biomedicine and Prevention, Università degli Studi di Roma Tor Vergata Roma, Italia = University of Rome Tor Vergata Rome, Italy = Université de Rome Tor Vergata Rome, Italie, Università Campus Bio-Medico di Roma, Partenaires INRAE, Università degli studi 'G. d'Annunzio' Chieti-Pescara Chieti-Pescara (Ud'A), Flanders Institute for Biotechnology, Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital Lausanne (CHUV), MIUR (PRIN) 2012A9T2S9_004, Fondazione Cariplo, Associazione Italiana Sindrome X Fragile, Telethon GGP15257, Lejeune Foundation, Filippini, A, Bonini, D, Lacoux, C, Pacini, L, Zingariello, M, Sancillo, L, Bosisio, D, Salvi, V, Mingardi, J, La Via, L, Zalfa, F, Bagni, C, Barbon, A
Quelle: RNA Biol
RNA biology, vol. 14, no. 11, pp. 1580-1591
Verlagsinformationen: Informa UK Limited, 2017.
Publikationsjahr: 2017
Schlagwörter: Male, 0301 basic medicine, RNA editing, Adenosine Deaminase, Knockout, [SDV]Life Sciences [q-bio], Messenger, Adenosine Deaminase/genetics, Adenosine Deaminase/metabolism, Animals, Cell Nucleus/metabolism, Cell Nucleus/ultrastructure, Cerebral Cortex/metabolism, Cerebral Cortex/pathology, Disease Models, Animal, Fragile X Mental Retardation Protein/genetics, Fragile X Mental Retardation Protein/metabolism, Fragile X Syndrome/genetics, Fragile X Syndrome/metabolism, Fragile X Syndrome/pathology, Gene Deletion, Hippocampus/metabolism, Hippocampus/pathology, Humans, Mice, Mice, Knockout, Neurons/metabolism, Neurons/pathology, Phenotype, Primary Cell Culture, Protein Binding, RNA Editing, RNA, Messenger/genetics, RNA, Messenger/metabolism, RNA-Binding Proteins/genetics, RNA-Binding Proteins/metabolism, ADAR2, FMRP, Fragile X syndrome, Molecular Biology, Cell Biology, RNA-Binding Protein, Hippocampus, Fragile X Mental Retardation Protein, 03 medical and health sciences, Hippocampu, Settore BIO/13 - BIOLOGIA APPLICATA, RNA, Messenger, Cell Nucleu, RNA editing, FMRP, Cell Nucleus, Cerebral Cortex, Neurons, 0303 health sciences, Animal, RNA-Binding Proteins, Neuron, [SDV] Life Sciences [q-bio], Fragile X Syndrome, Disease Models, RNA, Human, Research Paper
Beschreibung: The fragile X syndrome (FXS), the most common form of inherited intellectual disability, is due to the absence of FMRP, a protein regulating RNA metabolism. Recently, an unexpected function of FMRP in modulating the activity of Adenosine Deaminase Acting on RNA (ADAR) enzymes has been reported both in Drosophila and Zebrafish. ADARs are RNA-binding proteins that increase transcriptional complexity through a post-transcriptional mechanism called RNA editing. To evaluate the ADAR2-FMRP interaction in mammals we analyzed several RNA editing re-coding sites in the fmr1 knockout (KO) mice. Ex vivo and in vitro analysis revealed that absence of FMRP leads to an increase in the editing levels of brain specific mRNAs, indicating that FMRP might act as an inhibitor of editing activity. Proximity Ligation Assay (PLA) in mouse primary cortical neurons and in non-neuronal cells revealed that ADAR2 and FMRP co-localize in the nucleus. The ADAR2-FMRP co-localization was further observed by double-immunogold Electron Microscopy (EM) in the hippocampus. Moreover, ADAR2-FMRP interaction appeared to be RNA independent. Because changes in the editing pattern are associated with neuropsychiatric and neurodevelopmental disorders, we propose that the increased editing observed in the fmr1-KO mice might contribute to the FXS molecular phenotypes.
Publikationsart: Article
Other literature type
Conference object
Dateibeschreibung: application/pdf
Sprache: English
ISSN: 1555-8584
1547-6286
DOI: 10.1080/15476286.2017.1338232
DOI: 10.6084/m9.figshare.5139259.v1
DOI: 10.6084/m9.figshare.5139259
Zugangs-URL: https://www.tandfonline.com/doi/pdf/10.1080/15476286.2017.1338232?needAccess=true
https://pubmed.ncbi.nlm.nih.gov/28640668
https://pubmed.ncbi.nlm.nih.gov/28640668/
https://serval.unil.ch/resource/serval:BIB_3F5DA390795D.P001/REF.pdf
https://core.ac.uk/display/149488223
http://europepmc.org/articles/PMC5785225
https://www.tandfonline.com/doi/full/10.1080/15476286.2017.1338232
https://www.tandfonline.com/doi/pdf/10.1080/15476286.2017.1338232
http://www.tandfonline.com/toc/krnb20/current
https://doi.org/10.1080/15476286.2017.1338232
https://hdl.handle.net/11564/675464
https://hdl.handle.net/10281/383992
http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_3F5DA390795D7
https://serval.unil.ch/notice/serval:BIB_3F5DA390795D
https://serval.unil.ch/resource/serval:BIB_3F5DA390795D.P001/REF.pdf
https://hdl.handle.net/11379/513375
Rights: CC BY NC ND
CC BY
Dokumentencode: edsair.doi.dedup.....2c40c3e79b9fdb4f78e85c082a4eb63e
Datenbank: OpenAIRE
Beschreibung
Abstract:The fragile X syndrome (FXS), the most common form of inherited intellectual disability, is due to the absence of FMRP, a protein regulating RNA metabolism. Recently, an unexpected function of FMRP in modulating the activity of Adenosine Deaminase Acting on RNA (ADAR) enzymes has been reported both in Drosophila and Zebrafish. ADARs are RNA-binding proteins that increase transcriptional complexity through a post-transcriptional mechanism called RNA editing. To evaluate the ADAR2-FMRP interaction in mammals we analyzed several RNA editing re-coding sites in the fmr1 knockout (KO) mice. Ex vivo and in vitro analysis revealed that absence of FMRP leads to an increase in the editing levels of brain specific mRNAs, indicating that FMRP might act as an inhibitor of editing activity. Proximity Ligation Assay (PLA) in mouse primary cortical neurons and in non-neuronal cells revealed that ADAR2 and FMRP co-localize in the nucleus. The ADAR2-FMRP co-localization was further observed by double-immunogold Electron Microscopy (EM) in the hippocampus. Moreover, ADAR2-FMRP interaction appeared to be RNA independent. Because changes in the editing pattern are associated with neuropsychiatric and neurodevelopmental disorders, we propose that the increased editing observed in the fmr1-KO mice might contribute to the FXS molecular phenotypes.
ISSN:15558584
15476286
DOI:10.1080/15476286.2017.1338232