Autism-Risk Gene necab2 Regulates Psychomotor and Social Behavior as a Neuronal Modulator of mGluR1 Signaling
文献类型： 外文期刊
作者： Chen, Zexu 1 ; Long, Han 1 ; Guo, Jianhua 1 ; Wang, Yiran 1 ; He, Kezhe 1 ; Tao, Chenchen 6 ; Li, Xiong 1 ; Jiang, Keji 9 ; Guo, Su 7 ; Pi, Yan 1 ;
作者机构： 1.Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai, Peoples R China
2.Fudan Univ, Natl Demonstrat Ctr Expt Biol Educ, Sch Life Sci, Shanghai, Peoples R China
3.Fudan Univ, Eye Inst, Shanghai, Peoples R China
4.Fudan Univ, Eye & ENT Hosp, Dept Ophthalmol, Shanghai, Peoples R China
5.Fudan Univ, Chinese Acad Med Sci, NHC Key Lab Myopia, Key Lab Myopia, Shanghai, Peoples R China
6.Fudan Univ, Shanghai Med Coll, Sch Clin Med, Shanghai, Peoples R China
7.Univ California San Francisco, Dept Bioengn & Therapeut Sci, Programs Human Genet & Biol Sci, San Francisco, CA 94143 USA
8.Fudan Univ, Zhongshan Hosp, Dept Pulm & Crit Care Med, Shanghai, Peoples R China
9.Chinese Acad Fishery Sci, East China Sea Fisheries Res Inst, Shanghai, Peoples R China
关键词： autism spectrum disorders; calcium-binding protein; social behavior; metabotropic glutamate receptor 1; cerebellum
期刊名称：FRONTIERS IN MOLECULAR NEUROSCIENCE （ 2021影响因子：6.261； 五年影响因子：6.187 ）
ISSN： 1662-5099
年卷期： 2022 年 15 卷
收录情况： SCI
摘要： Background: De novo deletion of the neuronal calcium-binding protein 2 (NECAB2) locus is associated with idiopathic autism spectrum disorders (ASDs). The in vivo function of NECAB2 in the brain remains largely elusive. Methods: We investigated the morphological and behavioral profiles of both necab2 knock-out and overexpression zebrafish models. The expression pattern and molecular role of necab2 were probed through a combination of in vitro and in vivo assays. Results: We show that Necab2 is a neuronal specific, cytoplasmic, and membrane-associated protein, abundantly expressed in the telencephalon, habenula, and cerebellum. Necab2 is distributed pen-synaptically in subsets of glutamatergic and GABAergic neurons. CRISPR/Cas9-generated necab2 knock-out zebrafish display normal morphology but exhibit a decrease in locomotor activity and thigmotaxis with impaired social interaction only in males. Conversely, necab2 overexpression yields behavioral phenotypes opposite to the loss-of-function. Proteomic profiling uncovers a role of Necab2 in modulating signal transduction of G-protein coupled receptors. Specifically, co-immunoprecipitation, immunofluorescence, and confocal live-cell imaging suggest a complex containing NECAB2 and the metabotropic glutamate receptor 1 (mGluR1). In vivo measurement of phosphatidylinositol 4,5-bisphosphate further substantiates that Necab2 promotes mGluR1 signaling. Conclusions: Necab2 regulates psychomotor and social behavior via modulating a signaling cascade downstream of mGluR1.
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