Abstract
ABSTRACTDISRUPTED-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.
Highlights
Since its discovery in 2000, DISRUPTED-IN-SCHIZOPHRENIA (DISC1) has been one of the most widely studied genetic risk factors for mental illness
Expression of disc1 is altered in Sonic hedgehog (Shh) pathway mutant embryos To determine whether levels of Shh signalling influence disc1 expression in the CNS, disc1 expression was analysed in Hedgehog (Hh) pathway mutant embryos
We utilised three stable genetic mutant lines: smob641 loss-of-function mutants carrying a mutation in the Smoothened (Smo) receptor leading to complete loss of Shh signal transduction (Varga et al, 2001); iguts294e mutants that have a mutation in DAZ-interacting protein 1 (DZIP1) leading to ciliary defects and subsequent aberrations in Shh signal transduction (Brand et al, 1996); and ptch1;ptch2 loss-of-function double mutants which harbour mutations in both Patched1 and Patched2 leading to constitutive activation of Shh signalling (Koudijs et al, 2008)
Summary
Since its discovery in 2000, DISRUPTED-IN-SCHIZOPHRENIA (DISC1) has been one of the most widely studied genetic risk factors for mental illness. It was discovered through positional mapping of. The DISC1 gene contains 13 exons and encodes an 854 amino acid protein with a highly conserved C-terminal region containing multiple coiled-coil motifs. The translocation breakpoint is situated between exons 8 and 9, thereby disrupting the conserved coiled-coil region which is important for interaction with a number of proteins important in neurodevelopment, including NDEL1, NDE1 and LIS1 (Millar et al, 2003; Morris et al, 2003; Ozeki et al, 2003). It may be the case that while perturbation of DISC1 function is causal in the Scottish family, alterations in upstream and downstream signalling pathways may be more relevant to mental health issues in the wider population
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