Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan.
Sci Rep. 2011;1:16. doi: 10.1038/srep00016. Epub 2011 Jun 17.
ZIC2 is a causal gene for holoprosencephaly and encodes a zinc-finger-type transcriptional regulator. We characterized Zic2(kd/+) mice with a moderate (40%) reduction in Zic2 expression. Zic2(kd/+) mice showed increased locomotor activity in novel environments, cognitive and sensorimotor gating dysfunctions, and social behavioral abnormalities. Zic2(kd/+) brain involved enlargement of the lateral ventricle, thinning of the cerebral cortex and corpus callosum, and decreased number of cholinergic neurons in the basal forebrain. Because these features are reminiscent of schizophrenia, we examined ZIC2 variant-carrying allele frequencies in schizophrenia patients and in controls in the Japanese population. Among three novel missense mutations in ZIC2, R409P was only found in schizophrenia patients, and was located in a strongly conserved position of the zinc finger domain. Mouse Zic2 with the corresponding mutation showed lowered transcription-activating capacity and had impaired target DNA-binding and co-factor-binding capacities. These results warrant further study of ZIC2 in the pathogenesis of schizophrenia.
ZIC2 是一种全前脑畸形的致病基因，编码一种锌指型转录调节因子。我们对 Zic2 表达中度降低（40%）的 Zic2(kd/+) 小鼠进行了表征。Zic2(kd/+) 小鼠在新环境中表现出更高的运动活性、认知和感觉运动门控功能障碍以及社会行为异常。Zic2(kd/+) 大脑涉及侧脑室扩大、大脑皮层和胼胝体变薄以及基底前脑胆碱能神经元数量减少。由于这些特征类似于精神分裂症，我们在日本人群中的精神分裂症患者和对照组中检查了 ZIC2 变异等位基因的频率。在 ZIC2 的三个新的错义突变中，只有 R409P 仅在精神分裂症患者中发现，并且位于锌指结构域的强保守位置。具有相应突变的小鼠 Zic2 显示出转录激活能力降低，并且靶 DNA 结合和共因子结合能力受损。这些结果表明需要进一步研究 ZIC2 在精神分裂症发病机制中的作用。
