Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin.
Jun MaLu-Qing ZhangZi-Xuan HeXiao-Xiao HeYa-Jun WangYou-Li JianXin WangBin-Bin ZhangCe SuJun LuBai-Qu HuangYu ZhangGui-Yun WangWei-Xiang GuoDe-Lai QiuLin MeiWen-Cheng XiongYao-Wu ZhengXiao-Juan ZhuPublished in: PLoS biology (2019)
Dendritic spine development is crucial for the establishment of excitatory synaptic connectivity and functional neural circuits. Alterations in spine morphology and density have been associated with multiple neurological disorders. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. However, the role of DIP2A in the brain remains largely unknown. In this study, we found that deletion of Dip2a in mice induced defects in spine morphogenesis along with thin postsynaptic density (PSD), and reduced synaptic transmission of pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin. Furthermore, Dip2a knockout (KO) mice exhibited autism-like behaviors, including excessive repetitive behaviors and defects in social novelty. Importantly, acetylation mimetic cortactin restored the impaired synaptic transmission and ameliorated repetitive behaviors in these mice. Altogether, our findings establish an initial link between DIP2A gene variations in autism spectrum disorder (ASD) and highlight the contribution of synaptic protein acetylation to synaptic processing.
Keyphrases
- autism spectrum disorder
- intellectual disability
- resting state
- prefrontal cortex
- attention deficit hyperactivity disorder
- high fat diet induced
- copy number
- white matter
- functional connectivity
- genome wide
- spinal cord
- high frequency
- binding protein
- mental health
- healthcare
- protein protein
- histone deacetylase
- genome wide identification
- metabolic syndrome
- spinal cord injury
- oxidative stress
- working memory
- blood brain barrier
- adipose tissue
- stress induced
- dna methylation
- genome wide analysis
- protein kinase