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.
journal_name
Naturejournal_title
Natureauthors
Parras A,Anta H,Santos-Galindo M,Swarup V,Elorza A,Nieto-González JL,Picó S,Hernández IH,Díaz-Hernández JI,Belloc E,Rodolosse A,Parikshak NN,Peñagarikano O,Fernández-Chacón R,Irimia M,Navarro P,Geschwind DH,Méndez R,Ldoi
10.1038/s41586-018-0423-5subject
Has Abstractpub_date
2018-08-01 00:00:00pages
441-446issue
7719eissn
0028-0836issn
1476-4687pii
10.1038/s41586-018-0423-5journal_volume
560pub_type
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