Human Molecular Genetics Advance Access originally published online on November 7, 2008
Human Molecular Genetics 2009 18(3):391-404; doi:10.1093/hmg/ddn361
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Disrupted-in-schizophrenia 1 and neuregulin 1 are required for the specification of oligodendrocytes and neurones in the zebrafish brain
1 MRC Centre for Developmental and Biomedical Genetics 2 Section of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield S10 2RX, UK 3 Division of Neurobiology, Department of Psychiatry, and Departments of Neurology and Neuroscience, The Johns Hopkins University, Baltimore, MD, USA 4 Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK
* To whom correspondence should be addressed. Tel: +44 1142261311; Fax: +44 1142261201; Email: j.d.wood1{at}shef.ac.uk
Received October 3, 2008; Accepted October 29, 2008
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.
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