Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing
Author
Parras, Alberto; Anta, Héctor; Santos-Galindo, María; Swarup, Vivek; Elorza, Ainara; Nieto-González, José L.; Picó, Sara; Hernández, Ivó H.; Díaz-Hernández, Juan I.; Belloc, Eulàlia; Rodolosse, Annie; Parikshak, Neelroop N.; Peñagarikano, Olga; Fernández-Chacón, Rafael; Irimia, Manuel; Navarro, Pilar; Geschwind, Daniel H.; Méndez, Raúl; Lucas, José J.Entity
UAM. Departamento de BiologíaPublisher
Nature ResearchDate
2018-08-23Citation
10.1038/s41586-018-0423-5
Nature 560.7719 (2018): 441-446
ISSN
0028-0836 (print); 1476-4687 (online)DOI
10.1038/s41586-018-0423-5Funded by
This work was supported by grants: ISCIII-CiberNed-PI2013/09- 412 &PI2015-2/06 (J.J.L., R.F.-C), -FEDER-PI14/00125&PI17/00199 (P.N.); MINECO413 SAF2012-34177&SAF2015-65371-R (J.J.L.) -FEDER-BFU2014-54122-P (R.M.) - 414 BFU2014-55076-P (M.I.) -BFU2016-76050-P (R.F.-C.), -SEV-2012-0208 to CRG by 415 European Union FEDER (M.I.); NIMH 5R37 MH060233, 5R01 MH09714 and 5R01 416 MH100027 (D.H.G.); Junta de Andalucía-P12-CTS-2232&CTS-600 (R.F.-C.); Generalitat 417 de Catalunya-2014/SGR/143 (P.N.); ERC-StG-LS2-637591 (M.I.); and by Fundación 418 Botín-Banco Santander/Santander Universities Global Division, Fundación BBVA, and 419 Fundación Ramón Areces; A.P. was recipient of a MICINN FPI-fellowship; N.N.P. (NRSA 420 F30 MH099886, UCLA Medical Scientist Training Program) and V.S. (Larry Hillblom 421 Postdoctoral Fellowship)Project
Gobierno de España. SAF2012-34177; Gobierno de España. SAF2015-65371-R; Gobierno de España. BFU2014-54122-P; Gobierno de España. BFU2014-55076-P; Gobierno de España. BFU2016-76050-P; Gobierno de España. SEV-2012-0208; info:eu-repo/grantAgreement/EC/H2020/637591Editor's Version
http://doi.org/10.1038/s41586-018-0423-5Subjects
Autism; Polyadenylation; RNA, Messenger; cytoplasmic polyadenylation; Biología y Biomedicina / BiologíaRights
© 2018, Springer Nature LimitedAbstract
Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1–4 (CPEB1–4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes
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Google Scholar:Parras, Alberto
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Anta, Héctor
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Santos-Galindo, María
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Swarup, Vivek
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Elorza, Ainara
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Nieto-González, José L.
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Picó, Sara
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Hernández, Ivó H.
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Díaz-Hernández, Juan I.
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Belloc, Eulàlia
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Rodolosse, Annie
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Parikshak, Neelroop N.
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Peñagarikano, Olga
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Fernández-Chacón, Rafael
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Irimia, Manuel
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Navarro, Pilar
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Geschwind, Daniel H.
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Méndez, Raúl
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Lucas, José J.
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