Sakae Nobutaka, Yamasaki Nobuyuki, Kitaichi Kiyoyuki, Fukuda Takaichi, Yamada Mitsunori, Yoshikawa Hiroo, Hiranita Takato, Tatsumi Yoshiki, Kira Jun-ichi, Yamamoto Tsuneyuki, Miyakawa Tsuyoshi, Nakayama Keiichi I
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-2-2 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Hum Mol Genet. 2008 Oct 15;17(20):3191-203. doi: 10.1093/hmg/ddn215. Epub 2008 Jul 22.
FEZ1 (fasciculation and elongation protein zeta 1), a mammalian ortholog of Caenorhabditis elegans UNC-76, interacts with DISC1 (disrupted in schizophrenia 1), a schizophrenia susceptibility gene product, and polymorphisms of human FEZ1 have been associated with schizophrenia. We have now investigated the role of FEZ1 in brain development and the pathogenesis of schizophrenia by generating mice that lack Fez1. Immunofluorescence staining revealed FEZ1 to be located predominantly in gamma-aminobutyric acid-containing interneurons. The Fez1(-/-) mice showed marked hyperactivity in a variety of behavioral tests as well as enhanced behavioral responses to the psychostimulants MK-801 and methamphetamine. In vivo microdialysis revealed that the methamphetamine-induced release of dopamine in the nucleus accumbens was exaggerated in the mutant mice, suggesting that enhanced mesolimbic dopaminergic transmission contributes to their hyperactivity phenotype. These observations implicate impairment of FEZ1 function in the pathogenesis of schizophrenia.
FEZ1（成束和延伸蛋白ζ1）是秀丽隐杆线虫UNC-76在哺乳动物中的同源物，它与精神分裂症易感基因产物DISC1（精神分裂症相关1）相互作用，并且人类FEZ1的多态性与精神分裂症有关。我们现在通过培育缺乏Fez1的小鼠，研究了FEZ1在大脑发育和精神分裂症发病机制中的作用。免疫荧光染色显示FEZ1主要位于含γ-氨基丁酸的中间神经元中。Fez1基因敲除小鼠在各种行为测试中表现出明显的多动，以及对精神兴奋剂MK-801和甲基苯丙胺的行为反应增强。体内微透析显示，突变小鼠中甲基苯丙胺诱导的伏隔核多巴胺释放增加，这表明中脑边缘多巴胺能传递增强导致了它们的多动表型。这些观察结果表明FEZ1功能受损与精神分裂症的发病机制有关。
