Tee Jing Yang, Sutharsan Ratneswary, Fan Yongjun, Mackay-Sim Alan
Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
Mol Cell Neurosci. 2017 Apr;80:111-122. doi: 10.1016/j.mcn.2017.03.005. Epub 2017 Mar 9.
Schizophrenia is a highly heritable psychiatric disorder linked to a large number of risk genes. The function of these genes in disease etiology is not fully understood but pathway analyses of genomic data suggest developmental dysregulation of cellular processes such as neuronal migration and axon guidance. Previous studies of patient-derived olfactory cells show them to be more motile than control-derived cells when grown on a fibronectin substrate, motility that is dependent on focal adhesion kinase signaling. The aim of this study was to investigate whether schizophrenia patient-derived cells are responsive to other extracellular matrix (ECM) proteins that bind integrin receptors. Olfactory neurosphere-derived cells from nine patients and nine matched controls were grown on ECM protein substrates at increasing concentrations and their movement was tracked for 24h using automated high-throughput imaging. Control-derived cells increased their motility as the ECM substrate concentration increased, whereas patient-derived cell motility was little affected by ECM proteins. Patient and control cells had appropriate integrin receptors for these ECM substrates and detected them as shown by increases in focal adhesion number and size in response to ECM proteins, which also induced changes in cell morphology and cytoskeleton. These observations indicate that patient cells failed to translate the detection of ECM proteins into appropriate changes in cell motility. In a sense, patient cells act like a moving car whose accelerator is jammed, moving at the same speed without regard to the external environment. This focuses attention on cell motility regulation rather than speed as key to impairment of neuronal migration in the developing brain in schizophrenia.
精神分裂症是一种高度可遗传的精神疾病，与大量风险基因相关。这些基因在疾病病因中的功能尚未完全了解，但基因组数据的通路分析表明，细胞过程如神经元迁移和轴突导向存在发育失调。先前对患者来源的嗅觉细胞的研究表明，当在纤连蛋白底物上生长时，它们比对照来源的细胞更具运动性，这种运动性依赖于粘着斑激酶信号传导。本研究的目的是调查精神分裂症患者来源的细胞是否对其他结合整合素受体的细胞外基质（ECM）蛋白有反应。来自9名患者和9名匹配对照的嗅觉神经球衍生细胞在浓度不断增加的ECM蛋白底物上生长，并使用自动高通量成像跟踪它们24小时的运动。对照来源的细胞随着ECM底物浓度的增加而增加其运动性，而患者来源的细胞运动性几乎不受ECM蛋白的影响。患者和对照细胞对这些ECM底物具有合适的整合素受体，并如通过粘着斑数量和大小的增加所显示的那样检测到它们，这也诱导了细胞形态和细胞骨架的变化。这些观察结果表明，患者细胞未能将对ECM蛋白的检测转化为细胞运动性的适当变化。从某种意义上说，患者细胞就像一辆油门卡住的行驶中的汽车，以相同的速度行驶而不考虑外部环境。这将注意力集中在细胞运动性调节而非速度上，认为这是精神分裂症发育中大脑神经元迁移受损的关键。
