Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin

Autor: Luqing Zhang, Baiqu Huang, Gui-Yun Wang, Zi-Xuan He, Xin Wang, Jun Ma, Xiao-Xiao He, De-Lai Qiu, Jun Lu, Youli Jian, Weixiang Guo, Yu Zhang, Yaowu Zheng, Bin-Bin Zhang, Lin Mei, Wen Cheng Xiong, Ya-Jun Wang, Ce Su, Xiaojuan Zhu
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Candidate gene
Pervasive Developmental Disorders
Dendritic spine
Autism Spectrum Disorder
Amino Acid Motifs
Social Sciences
Synaptic Transmission
Biochemistry
Mice
0302 clinical medicine
Animal Cells
Morphogenesis
Medicine and Health Sciences
Psychology
Post-Translational Modification
Biology (General)
Regulation of gene expression
Mice
Knockout
Neurons
Mammals
Cerebral Cortex
Animal Behavior
Neuronal Morphology
General Neuroscience
Pyramidal Cells
Chemical Reactions
Gene Expression Regulation
Developmental
Nuclear Proteins
Eukaryota
Brain
Acetylation
Cell biology
Chemistry
Physical Sciences
Vertebrates
Excitatory postsynaptic potential
Cellular Types
Anatomy
General Agricultural and Biological Sciences
Cortactin
Protein Binding
Research Article
QH301-705.5
Dendritic Spines
Neurotransmission
Biology
Rodents
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Acetyl Coenzyme A
Biological neural network
Animals
Protein Interaction Domains and Motifs
Behavior
Binding Sites
General Immunology and Microbiology
Genetic Complementation Test
Organisms
Post-Synaptic Density
Biology and Life Sciences
Proteins
Cell Biology
Neuronal Dendrites
Embryo
Mammalian
Disease Models
Animal
030104 developmental biology
Animals
Newborn
Cellular Neuroscience
Amniotes
Developmental Psychology
biology.protein
Postsynaptic density
Protein Processing
Post-Translational
Zoology
030217 neurology & neurosurgery
Neuroscience
Zdroj: PLoS Biology, Vol 17, Iss 10, p e3000461 (2019)
PLoS Biology
ISSN: 1545-7885
1544-9173
Popis: 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.
The autism candidate gene DIP2A is known to be involved in the synthesis of acetylated coenzyme A, but its precise role in the brain remains largely unknown. This study shows that loss of DIP2A in mice results in an imbalance in the acetylation of the synaptic protein cortactin, causing defects in spine morphogenesis and synaptic transmission that may establish a link to autism spectrum disorders.
Databáze: OpenAIRE
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