16p11.2 CNV gene Doc2α functions in neurodevelopment and social behaviors through interaction with Secretagogin

• Published in: Cell reports (Cambridge) Vol. 42; no. 7; p. 112691
• Main Authors: Wang, Qiu-Wen, Qin, Junhong, Chen, Yan-Fen, Tu, Yingfeng, Xing, Yun-Yun, Wang, Yuchen, Yang, Lv-Yu, Lu, Si-Yao, Geng, Libo, Shi, Wei, Yang, Yiming, Yao, Jun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.07.2023; Elsevier
• Subjects: 16p11.2; Animals; Autism Spectrum Disorder - genetics; Chromosome Deletion; Chromosomes, Human, Pair 16 - genetics; CP: Developmental biology; CP: Neuroscience; DNA Copy Number Variations - genetics; Doc2α; Humans; Mice; neurodevelopmental disorder; SCGN; Schizophrenia - genetics; Secretagogins - genetics; Social Behavior; SCGN; Doc2α; neurodevelopmental disorder; CP: Neuroscience; social behavior; 16p11.2; CP: Developmental biology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112691

Copy-number variations (CNVs) of the human 16p11.2 genetic locus are associated with neurodevelopmental disorders, including autism spectrum disorders (ASDs) and schizophrenia. However, it remains largely unclear how this locus is involved in the disease pathogenesis. Doc2α is localized within this locus. Here, using in vivo and ex vivo electrophysiological and morphological approaches, we show that Doc2α-deficient mice have neuronal morphological abnormalities and defects in neural activity. Moreover, the Doc2α-deficient mice exhibit social and repetitive behavioral deficits. Furthermore, we demonstrate that Doc2α functions in behavioral and neural phenotypes through interaction with Secretagogin (SCGN). Finally, we demonstrate that SCGN functions in social/repetitive behaviors, glutamate release, and neuronal morphology of the mice through its Doc2α-interacting activity. Therefore, Doc2α likely contributes to neurodevelopmental disorders through its interaction with SCGN. [Display omitted] •Doc2α KO mice exhibit neurodevelopmental deficits and autistic-like behaviors•Doc2α functions through direct interaction with SCGN via its linker domain•The interaction between Doc2α and SCGN is critical for the function of Doc2α Wang et al. show that Doc2α-deficient mice exhibited social and repetitive behavioral deficits, whereas disrupting the interaction of Doc2α with SCGN induces behavioral and neural phenotypes. Thus, Doc2α likely contributes to neurodevelopmental disorders through its interaction with SCGN.