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Title: Sonic hedgehog functions upstream of disrupted-in-schizophrenia 1 (disc1): Implications for mental illness
Authors: Boyd, P.J
Cunliffe, V.T
Roy, S 
Wood, J.D
Keywords: cyclopamine
disrupted in schizophrenia 1 protein
mutant protein
protein Patched 1
protein Patched 2
sonic hedgehog protein
animal cell
animal embryo
animal tissue
cell labeling
controlled study
immunofluorescence test
in situ hybridization
mental disease
molecular pathology
oligodendrocyte precursor cell
protein expression
protein function
quantitative analysis
reverse transcription polymerase chain reaction
signal transduction
zebra fish
Issue Date: 2015
Citation: Boyd, P.J, Cunliffe, V.T, Roy, S, Wood, J.D (2015). Sonic hedgehog functions upstream of disrupted-in-schizophrenia 1 (disc1): Implications for mental illness. Biology Open 4 (10) : 1336-1343. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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. © 2015. Published by The Company of Biologists Ltd.
Source Title: Biology Open
ISSN: 20466390
DOI: 10.1242/bio.012005
Rights: Attribution 4.0 International
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