The autism risk gene CNTN4 modulates dendritic spine formation

Zhao, Rongjuan1,2; Zhu, Tengfei3,4; Liu, Qiong5,6; Tian, Qi1,2; Wang, Meng1,2; Chen, Jingjing7; Tong, Dali8; Yu, Bin8; Guo, Hui1,2,9; Xia, Kun1,2,9,10; Qiu, Zilong8,10; Hu, Zhengmao1,2,9

2022-01-15

10.1093/hmg/ddab233

HUMAN MOLECULAR GENETICS   影响因子和分区

0964-6906

1460-2083

Contactin 4 (CNTN4) is a crucial synaptic adhesion protein that belongs to the contactin superfamily. Evidence from both human genetics and mouse models suggests that synapse formation and structural deficits strongly correlate with neurodevelopmental disorders, including autism. In addition, several lines of evidence suggest that CNTN4 is associated with the risk of autism. However, the biological functions of CNTN4 in neural development and disease pathogenesis are poorly understood. In this study, we investigated whether and how CNTN4 is autonomously involved in the development of dendrites and dendritic spines in cortical neurons. Disruption of Cntn4 decreased the number of excitatory synapses, which led to a reduction in neural activity. Truncated proteins lacking the signal peptide, FnIII domains or GPI domain lacked the ability to regulate dendritic spine formation, indicating that CNTN4 regulates dendritic spine density through a mechanism dependent on FnIII domains. Importantly, we revealed that autism-related variants lacked the ability to regulate spine density and neural activity. In conclusion, our study suggests that CNTN4 is essential for promoting dendrite growth and dendritic spine formation and that disruptive variants of CNTN4 interfere with abnormal synapse formation and may increase the risk of autism.

SCI

英语

其他

National Natural Science Foundation of China[81671122,81730036,81871079] ; Science and Technology Major Projects of Hunan Province Science and Technology Department["2019SK2051","2019JJ40408","2018DK2016","2018SK1030"]

Biochemistry & Molecular Biology ; Genetics & Heredity

Biochemistry & Molecular Biology ; Genetics & Heredity

WOS:000743922000005

OXFORD UNIV PRESS

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Cent South Univ, Ctr Med Genet, Sch Life Sci, Changsha 410008, Hunan, Peoples R China
2.Cent South Univ, Hunan Key Lab Med Genet, Sch Life Sci, Changsha 410008, Hunan, Peoples R China
3.Southern Univ Sci & Technol, Peoples Hosp Shenzhen 3, Dept Crit Care Med, Affiliated Hosp 2, Shenzhen 518000, Peoples R China
4.Southeast Univ, Zhongda Hosp, Sch Med, Dept Crit Care Med, Nanjing 210000, Peoples R China
5.Cent South Univ, Xiangya Hosp, Dept Neurol, Changsha 410008, Peoples R China
6.Cent South Univ, Xiangya Hosp, Key Lab Hunan Prov Neurodegenerat Disorders, Changsha 410008, Peoples R China
7.Cent South Univ, Xiangya Hosp, Reprod Med Ctr, Changsha 410008, Hunan, Peoples R China
8.Chinese Acad Sci, Ctr Excellence Brain Sci & Intelligence Technol, Inst Neurosci, State Key Lab Neurosci, Shanghai 200031, Peoples R China
9.Cent South Univ, Hunan Key Lab Anim Models Human Dis, Changsha 410008, Hunan, Peoples R China
10.Chinese Acad Sci, Ctr Excellence Brain Sci & Intelligences Technol, CAS Key Lab Primate Neurobiol, Shanghai 200031, Peoples R China

Zhao, Rongjuan,Zhu, Tengfei,Liu, Qiong,et al. The autism risk gene CNTN4 modulates dendritic spine formation[J]. HUMAN MOLECULAR GENETICS,2022,31(2).

Zhao, Rongjuan.,Zhu, Tengfei.,Liu, Qiong.,Tian, Qi.,Wang, Meng.,...&Hu, Zhengmao.(2022).The autism risk gene CNTN4 modulates dendritic spine formation.HUMAN MOLECULAR GENETICS,31(2).

Zhao, Rongjuan,et al."The autism risk gene CNTN4 modulates dendritic spine formation".HUMAN MOLECULAR GENETICS 31.2(2022).