FEZ1 与 DISC1 在调控神经元发育和精神分裂症风险中的相互作用。
Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia.
机构信息
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
出版信息
Neuron. 2011 Nov 17;72(4):559-71. doi: 10.1016/j.neuron.2011.09.032.
Abstract
Disrupted-in Schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here, we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia.
摘要
精神分裂症相关蛋白 1（DISC1）是一种主要精神障碍的易感基因，编码一种支架蛋白，对神经元发育有多种影响。目前尚不清楚 DISC1 如何调节神经元发育的不同方面。在这里，我们发现成束蛋白 Zeta-1（FEZ1）与 DISC1 相互作用，协同调节成年小鼠海马体中新神经元的树突生长，而该途径补充了平行的 DISC1-NDEL1 相互作用，调节新神经元的细胞定位和形态发生。此外，对两个独立的精神分裂症患者和健康对照组的遗传关联分析显示，FEZ1 和 DISC1 之间存在上位性相互作用，但 FEZ1 和 NDEL1 之间不存在上位性相互作用，与精神分裂症的风险相关。我们的研究结果支持这样一种模型，即 DISC1 通过与不同的细胞内伴侣相互作用来调节神经元发育的不同方面，这种上位性可能导致精神分裂症风险增加。
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