Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing

Alberto Parras, Héctor Anta, María Santos-Galindo, Vivek Swarup, Ainara Elorza, José L. Nieto-González, Sara Picó, Ivó H. Hernández, Juan I. Díaz-Hernández, Eulàlia Belloc, Annie Rodolosse, Neelroop N. Parikshak, Olga Peñagarikano, Rafael Fernández-Chacón, Manuel Irimia, Pilar Navarro, Daniel H. Geschwind, Raúl Méndez () and José J. Lucas ()
Additional contact information
Alberto Parras: Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM
Héctor Anta: Hospital del Mar Medical Research Institute (IMIM)
María Santos-Galindo: Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM
Vivek Swarup: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA
Ainara Elorza: Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM
José L. Nieto-González: Instituto de Salud Carlos III
Sara Picó: Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM
Ivó H. Hernández: Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM
Juan I. Díaz-Hernández: Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM
Eulàlia Belloc: Barcelona Institute of Science and Technology
Annie Rodolosse: Barcelona Institute of Science and Technology
Neelroop N. Parikshak: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA
Olga Peñagarikano: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA
Rafael Fernández-Chacón: Instituto de Salud Carlos III
Manuel Irimia: Barcelona Institute for Science and Technology
Pilar Navarro: Hospital del Mar Medical Research Institute (IMIM)
Daniel H. Geschwind: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA
Raúl Méndez: Barcelona Institute of Science and Technology
José J. Lucas: Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM

Nature, 2018, vol. 560, issue 7719, 441-446

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41586-018-0423-5

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