The DISC1 promoter: characterization and regulation by FOXP2

Disrupted in schizophrenia 1 (DISC1) is a leading candidate susceptibility gene for schizophrenia, bipolar dis-order and recurrent major depression, which has been implicated in other psychiatric illnesses of neurode-velopmental origin, including autism.DISC1 was initially identified at the breakpoint of a balancedchromosomal translocation, t(1;11) (q42.1;14.3), in a family with a high incidence of psychiatric illness.Carriers of the translocation show a 50% reduction in DISC1 protein levels, suggesting altered DISC1 expres-sion as a pathogenic mechanism in psychiatric illness. Altered DISC1 expression in the post-mortem brainsof individuals with psychiatric illness and the frequent implication of non-coding regions of the gene by as-sociation analysis further support this assertion. Here, we provide the first characterization of the DISC1 pro-moter region. Using dual luciferase assays, we demonstrate that a region2300 to 2177 bp relative to thetranscription start site (TSS) contributes positively toDISC1 promoter activity, while a region 2982 to2301 bp relative to the TSS confers a repressive effect. We further demonstrate inhibition of DISC1 promoteractivity and protein expression by forkhead-box P2 (FOXP2), a transcription factor implicated in speech andlanguage function. This inhibition is diminished by two distinct FOXP2 point mutations, R553H and R328X,which were previously found in families affected by developmental verbal dyspraxia. Our work identifiesan intriguing mechanistic link between neurodevelopmental disorders that have traditionally been viewedas diagnostically distinct but which do share varying degrees of phenotypic overlap.