Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin.
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 (...
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doaj-0b1fe266f7b745bd9afb27f06ddbf4042021-07-02T16:28:51ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852019-10-011710e300046110.1371/journal.pbio.3000461Autism 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 ZhuDendritic 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.https://doi.org/10.1371/journal.pbio.3000461 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin. PLoS Biology |
author_facet |
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 |
author_sort |
Jun Ma |
title |
Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin. |
title_short |
Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin. |
title_full |
Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin. |
title_fullStr |
Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin. |
title_full_unstemmed |
Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin. |
title_sort |
autism candidate gene dip2a regulates spine morphogenesis via acetylation of cortactin. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Biology |
issn |
1544-9173 1545-7885 |
publishDate |
2019-10-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.pbio.3000461 |
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