State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
Cell Rep. 2023 Jul 25;42(7):112691. doi: 10.1016/j.celrep.2023.112691. Epub 2023 Jun 22.
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.
人类 16p11.2 遗传位点的拷贝数变异 (CNVs) 与神经发育障碍有关，包括自闭症谱系障碍 (ASD) 和精神分裂症。然而，该基因座如何参与疾病发病机制在很大程度上仍不清楚。Doc2α 位于该基因座内。在这里，我们使用体内和体外电生理和形态学方法表明，Doc2α 缺陷型小鼠具有神经元形态异常和神经活动缺陷。此外，Doc2α 缺陷型小鼠表现出社交和重复行为缺陷。此外，我们证明 Doc2α 通过与 Secretagogin (SCGN) 的相互作用在行为和神经表型中发挥作用。最后，我们证明 SCGN 通过其与 Doc2α 相互作用的活性在小鼠的社交/重复行为、谷氨酸释放和神经元形态中发挥作用。因此，Doc2α 可能通过与 SCGN 的相互作用导致神经发育障碍。
