Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Neuron. 2011 Nov 17;72(4):545-58. doi: 10.1016/j.neuron.2011.09.030.
Disrupted in Schizophrenia-1 (DISC1) is a candidate gene for psychiatric disorders and has many roles during brain development. Common DISC1 polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure, and function; however, it is unknown how this occurs. Here, we demonstrate using mouse, zebrafish, and human model systems that DISC1 variants are loss of function in Wnt/GSK3β signaling and disrupt brain development. The DISC1 variants A83V, R264Q, and L607F, but not S704C, do not activate Wnt signaling compared with wild-type DISC1 resulting in decreased neural progenitor proliferation. In zebrafish, R264Q and L607F could not rescue DISC1 knockdown-mediated aberrant brain development. Furthermore, human lymphoblast cell lines endogenously expressing R264Q displayed impaired Wnt signaling. Interestingly, S704C inhibited the migration of neurons in the developing neocortex. Our data demonstrate DISC1 variants impair Wnt signaling and brain development and elucidate a possible mechanism for their role in neuropsychiatric phenotypes.
精神分裂症相关蛋白 1（DISC1）是精神疾病的候选基因，在大脑发育过程中具有多种作用。常见的 DISC1 多态性（变体）与神经精神表型有关，包括认知改变、大脑结构和功能；然而，其发生机制尚不清楚。在这里，我们使用小鼠、斑马鱼和人类模型系统证明，DISC1 变体在 Wnt/GSK3β信号中失活，并破坏大脑发育。与野生型 DISC1 相比，DISC1 变体 A83V、R264Q 和 L607F 不能激活 Wnt 信号，导致神经祖细胞增殖减少。在斑马鱼中，R264Q 和 L607F 不能挽救 DISC1 敲低介导的异常大脑发育。此外，内源性表达 R264Q 的人类淋巴母细胞系显示出 Wnt 信号受损。有趣的是，S704C 抑制了发育中皮质的神经元迁移。我们的数据表明，DISC1 变体破坏了 Wnt 信号和大脑发育，并阐明了它们在神经精神表型中作用的可能机制。
