title: Sonic hedgehog functions upstream of disrupted-in-schizophrenia 1 (disc1): implications for mental illness.
abstract: DISRUPTED-IN-SCHIZOPHRENIA (DISC1) has been one of the most intensively studied genetic risk factors for mental illness since it was discovered through positional mapping of a translocation breakpoint in a large Scottish family where a balanced chromosomal translocation was found to segregate with schizophrenia and affective disorders. While the evidence for it being central to disease pathogenesis in the original Scottish family is compelling, recent genome-wide association studies have not found evidence for common variants at the DISC1 locus being associated with schizophrenia in the wider population. It may therefore be the case that DISC1 provides an indication of biological pathways that are central to mental health issues and functional studies have shown that it functions in multiple signalling pathways. However, there is little information regarding factors that function upstream of DISC1 to regulate its expression and function. We herein demonstrate that Sonic hedgehog (Shh) signalling promotes expression of disc1 in the zebrafish brain. Expression of disc1 is lost in smoothened mutants that have a complete loss of Shh signal transduction, and elevated in patched mutants which have constitutive activation of Shh signalling. We previously demonstrated that disc1 knockdown has a dramatic effect on the specification of oligodendrocyte precursor cells (OPC) in the hindbrain and Shh signalling is known to be essential for the specification of these cells. We show that disc1 is prominently expressed in olig2-positive midline progenitor cells that are absent in smo mutants, while cyclopamine treatment blocks disc1 expression in these cells and mimics the effect of disc1 knock down on OPC specification. Various features of a number of psychiatric conditions could potentially arise through aberrant Hedgehog signalling. We therefore suggest that altered Shh signalling may be an important neurodevelopmental factor in the pathobiology of mental illness.
authors.affiliation: Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield S10 2HQ, UK Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673, Singapore Bateson Centre, Department of Biomedical Science, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK.
authors.forename: Penelope J
authors.initials: PJ
authors.lastname: Boyd
authors.affiliation: Bateson Centre, Department of Biomedical Science, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Cunliffe
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673, Singapore Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, 119288, Singapore j.d.wood1@sheffield.ac.uk sudipto@imcb.a-star.edu.sg.
authors.forename: Sudipto
authors.initials: S
authors.lastname: Roy
authors.affiliation: Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield S10 2HQ, UK Bateson Centre, Department of Biomedical Science, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK j.d.wood1@sheffield.ac.uk sudipto@imcb.a-star.edu.sg.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wood
keywords: CNS; DISC1; Mental illness; Sonic Hedgehog