Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin

Jun Ma; Lu-Qing Zhang; Zi-Xuan He; Xiao-Xiao He; Ya-Jun Wang; You-Li Jian; Xin Wang; Bin-Bin Zhang; Ce Su; Jun Lu; Bai-Qu Huang; Yu Zhang; Gui-Yun Wang; Wei-Xiang Guo; De-Lai Qiu; Lin Mei; Wen-Cheng Xiong; Yao-Wu Zheng; Xiao-Juan Zhu

doi:10.1371/journal.pbio.3000461

Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin

PLoS Biol. 2019 Oct 10;17(10):e3000461. doi: 10.1371/journal.pbio.3000461. eCollection 2019 Oct.

Authors

Jun Ma¹, Lu-Qing Zhang¹, Zi-Xuan He¹, Xiao-Xiao He¹, Ya-Jun Wang¹, You-Li Jian², Xin Wang³, Bin-Bin Zhang⁴, Ce Su¹, Jun Lu¹, Bai-Qu Huang¹, Yu Zhang¹, Gui-Yun Wang¹, Wei-Xiang Guo², De-Lai Qiu⁴, Lin Mei⁵, Wen-Cheng Xiong⁵, Yao-Wu Zheng¹, Xiao-Juan Zhu¹

Affiliations

¹ Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun, China.
² State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
³ School of Life Sciences, Yunnan University, Kunming, China.
⁴ Key Laboratory of Cellular Function and Pharmacology of Jilin Province, Yanbian University, Yanji, China.
⁵ Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, United States of America.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetyl Coenzyme A / deficiency
Acetyl Coenzyme A / genetics*
Acetylation
Amino Acid Motifs
Animals
Animals, Newborn
Autism Spectrum Disorder / genetics*
Autism Spectrum Disorder / metabolism
Autism Spectrum Disorder / physiopathology
Binding Sites
Cortactin / genetics*
Cortactin / metabolism
Dendritic Spines / metabolism*
Dendritic Spines / ultrastructure
Disease Models, Animal
Embryo, Mammalian
Gene Expression Regulation, Developmental
Genetic Complementation Test
Mice
Mice, Knockout
Morphogenesis / genetics*
Nuclear Proteins / deficiency
Nuclear Proteins / genetics*
Post-Synaptic Density / metabolism
Post-Synaptic Density / ultrastructure
Protein Binding
Protein Interaction Domains and Motifs
Protein Processing, Post-Translational*
Pyramidal Cells / metabolism
Pyramidal Cells / ultrastructure
Synaptic Transmission

Substances

Cortactin
Cttn protein, mouse
Dip2a protein, mouse
Nuclear Proteins
Acetyl Coenzyme A

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (31871040, 31601128 to XZ, http://www.nsfc.gov.cn/), Animal Model Research Grant of Jilin S&T (20191008009TC to XH, http://kjt.jl.gov.cn/), Program of International S and T Cooperation (2015DFA31580 to XZ, https://www.istcp.org.cn/), Fund for International Cooperation and Exchange of the Science Foundation of Jilin Province (20180414046GH to ZH, http://kjt.jl.gov.cn/), and the Fundamental Research Funds for the Central Universities (2412018JC010 to ZH, 2019005 to XZ, http://kjt.jl.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.