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

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.

A role of cellular translation regulation associated with toxic Huntingtin protein

“…In the human genome, almost 20% of the genes can be CPEB1 targets [4, 49]. In mice model for HD, CPEB3 and 4 were present in the insoluble proteome in relevant brain regions [23] and CPEB4 specific target mRNAs were found to be enriched in deadenylated transcripts [48]. Patients suffering from HD are also reported to have problems with memory [1, 8].…”

Modern human changes in regulatory regions implicated in cortical development

“…Tables S1 & S2). Among these, some well-studied disease-relevant genes are found: HTT (Huntington disease) [10], FOXP2 (language impairment) [11], CHD8 and CPEB4 (autism spectrum disorder) [12, 13], TCF4 (Pitt-Hopkins syndrome and schizophrenia) [14, 15], GLI3 (macrocephaly and Greig cephalopolysyndactyly syndrome) [16], PHC1 (primary, autosomal recessive, microcephaly-11) [17], RCAN1 (Down syndrome) [18], and DYNC1H1 (cortical malformations and microcephaly) [19].…”

MicroExonator enables systematic discovery and quantification of microexons across mouse embryonic development

“…Moreover, a recent genome-wide CRISPR-Cas9 screen has identified two additional factors, SRSF11 and RNPS1, that contribute to SRRM4-dependent microexon regulation, and these genes have also been implicated in ASD and other neurological disorders (Gonatopoulos-Pournatzis et al, 2018) . Another example of a protein where imbalances of microexon inclusion has been associated with elevated risk of ASD is cytoplasmic polyadenylation element binding protein 4 (CPEB4) (Parras et al, 2018) . We found differential inclusion of CPEB4 microexon during mouse embryonic brain development, and we also found microexon changes in other protein factors that are involved in mRNA polyadenylation, such as CPEB2, CPEB3 and FIP1L1.…”