Ren Jun, Zhao Tian, Xu Yiliang, Ye Haihong
Department of Medical Genetics and Developmental Biology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders, Center of Schizophrenia, Capital Medical University, Beijing 100069, China.
Department of Medical Genetics and Developmental Biology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders, Center of Schizophrenia, Capital Medical University, Beijing 100069, China.
Brain Res. 2016 Oct 1;1648(Pt A):290-297. doi: 10.1016/j.brainres.2016.06.033. Epub 2016 Jun 23.
Disrupted-in-schizophrenia 1 (DISC1), a gene susceptible for major mental illnesses, including schizophrenia, plays multiple roles in neural development, including neuronal proliferation, maturation, migration and neurite outgrowth. DISC1 regulates neurite length via interaction with several intracellular proteins, such as NDEL1, FEZ1 and dysbindin. However, the signal transduction mechanism upstream of DISC1 in regulating neurite outgrowth remains to be elucidated. Here we show that DISC1 interacts with the intracellular domain of close homolog of L1 (CHL1), a member of the L1 family of neural cell adhesion molecules. DISC1 and CHL1 proteins co-localize in growth cones of cortical neurons. Moreover, in neurite outgrowth assay, CHL1 rescues the inhibitory effect of DISC1 on the initial phase of neurite outgrowth. Considering the fact that CHL1 also plays crucial roles in neural development, and its coding gene is associated with schizophrenia, our findings indicate that DISC1 and CHL1 may engage in physical and functional interaction in neural development, supporting the notion that DISC1 regulates neurite outgrowth with a receptor belonging to the neural cell adhesion molecules, and disruption of such interaction may contribute to increased risk for schizophrenia.
精神分裂症缺失 1（DISC1）是一种与包括精神分裂症在内的主要精神疾病相关的基因，在神经发育中发挥多种作用，包括神经元增殖、成熟、迁移和神经突生长。DISC1 通过与多种细胞内蛋白相互作用来调节神经突长度，如 NDEL1、FEZ1 和失调结合蛋白。然而，DISC1 在调节神经突生长中的上游信号转导机制仍有待阐明。在此，我们表明 DISC1 与神经细胞黏附分子 L1 家族成员 L1 紧密同源物（CHL1）的细胞内结构域相互作用。DISC1 和 CHL1 蛋白在皮质神经元的生长锥中共定位。此外，在神经突生长试验中，CHL1 可挽救 DISC1 对神经突生长初始阶段的抑制作用。鉴于 CHL1 在神经发育中也起着关键作用，且其编码基因与精神分裂症相关，我们的研究结果表明，DISC1 和 CHL1 可能在神经发育中发生物理和功能相互作用，支持了 DISC1 通过一种属于神经细胞黏附分子的受体来调节神经突生长的观点，而这种相互作用的破坏可能会增加患精神分裂症的风险。
