精神分裂症相关基因1和神经调节蛋白1是斑马鱼大脑中少突胶质细胞和神经元特化所必需的。
Disrupted-in-schizophrenia 1 and neuregulin 1 are required for the specification of oligodendrocytes and neurones in the zebrafish brain.
作者信息
Wood Jonathan D, Bonath Franziska, Kumar Shashvita, Ross Christopher A, Cunliffe Vincent T
机构信息
MRC Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield S10 2RX, UK.
出版信息
Hum Mol Genet. 2009 Feb 1;18(3):391-404. doi: 10.1093/hmg/ddn361. Epub 2008 Nov 7.
Schizophrenia may arise from subtle abnormalities in brain development due to alterations in the functions of candidate susceptibility genes such as Disrupted-in-schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1). To provide novel insights into the functions of DISC1 in brain development, we mapped the expression of zebrafish disc1 and set out to characterize its role in early embryonic development using morpholino antisense methods. These studies revealed a critical requirement for disc1 in oligodendrocyte development by promoting specification of olig2-positive cells in the hindbrain and other brain regions. Since NRG1 has well-documented roles in myelination, we also analyzed the roles of nrg1 and ErbB signalling in zebrafish brain development and we observed strikingly similar defects to those seen in disc1 morphant embryos. In addition to their effects on oligodendrocyte development, knock-down of disc1 or nrg1 caused near total loss of olig2-positive cerebellar neurones, but caused no apparent loss of spinal motor neurones. These findings suggest that disc1 and nrg1 function in common or related pathways controlling development of oligodendrocytes and neurones from olig2-expressing precursor cells. Like DISC1 and NRG1, OLIG2 and ERBB4 are promising candidate susceptibility genes for schizophrenia. Hence our findings in the zebrafish embryo suggest that hitherto unappreciated neurodevelopmental connections may exist between key human schizophrenia susceptibility genes. These connections could be investigated in Disc1 and Nrg1 mouse models and in genetically defined groups of patients in order to determine whether they are relevant to the pathobiology of schizophrenia. GenBank accession number for Danio rerio disc1: EU273350.
精神分裂症可能源于大脑发育中的细微异常,这是由于诸如精神分裂症相关断裂基因1(DISC1)和神经调节蛋白1(NRG1)等候选易感基因功能的改变所致。为了深入了解DISC1在大脑发育中的功能,我们绘制了斑马鱼disc1的表达图谱,并着手使用吗啉代反义方法来表征其在早期胚胎发育中的作用。这些研究揭示了disc1在少突胶质细胞发育中的关键需求,它通过促进后脑和其他脑区中olig2阳性细胞的特化来实现这一需求。由于NRG1在髓鞘形成中具有充分记载的作用,我们还分析了nrg1和ErbB信号通路在斑马鱼大脑发育中的作用,并且我们观察到与disc1吗啡啉处理胚胎中所见缺陷极为相似的缺陷。除了对少突胶质细胞发育的影响外,敲低disc1或nrg1会导致olig2阳性小脑神经元几乎完全丧失,但不会导致脊髓运动神经元明显丧失。这些发现表明,disc1和nrg1在控制从表达olig2的前体细胞发育少突胶质细胞和神经元的共同或相关途径中发挥作用。与DISC1和NRG1一样,OLIG2和ERBB4是精神分裂症很有前景的候选易感基因。因此,我们在斑马鱼胚胎中的发现表明,关键的人类精神分裂症易感基因之间可能存在迄今未被认识到的神经发育联系。可以在Disc1和Nrg1小鼠模型以及基因定义的患者群体中研究这些联系,以确定它们是否与精神分裂症的病理生物学相关。斑马鱼disc1的GenBank登录号:EU273350。