Research Abstract


Zic2 hypomorphic mutant mice as a schizophrenia model and ZIC2 mutations identified in schizophrenia patients

2011年6月17日 Scientific Reports 1 : 16 doi: 10.1038/srep00016


畑山 実1*,石黒 亮1*,岩山佳美2,高嶋記子1,佐郡和人1,豊田倫子2,野崎弥生1,小高由梨1,山田一之3,吉川武男2 & 有賀 純1

  1. 理化学研究所 脳科学総合研究センター 行動発達障害研究チーム
  2. 理化学研究所 脳科学総合研究センター 分子精神科学研究チーム
  3. 理化学研究所 脳科学総合研究センター 動物資源開発支援ユニット
ZIC2 is a causal gene for holoprosencephaly and encodes a zinc-finger-type transcriptional regulator. We characterized Zic2kd/+ mice with a moderate (40%) reduction in Zic2 expression. Zic2kd/+ mice showed increased locomotor activity in novel environments, cognitive and sensorimotor gating dysfunctions, and social behavioral abnormalities. Zic2kd/+ 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.