Down-regulation of Dickkopf 3, a regulator of the Wnt signalling pathway, in elderly schizophrenic subjects.
The aetiology of schizophrenia is complex and the pathological mechanisms involved are still not fully understood. The aim of this project was to gain insight into the underlying molecular changes occurring in schizophrenia through the analysis of gene expression. Using suppression subtractive hybridization to isolate differentially expressed genes in superior temporal cortex (BA22), we detected one prominent sequence with reduced expression in schizophrenia and represented in at least nine clones. This was then selected for further validation. This 190-bp partial transcript showed identity to part of the Dickkopf-3 (Dkk3) gene sequence. Differential expression was initially confirmed in BA22 by slot blot hybridization where expression was decreased by 35% (p < 0.026). These results were further authenticated in a larger panel (12 control and 11 schizophrenia cases) using SYBR Green I real-time quantitative RT-PCR, in which a 41% decrease in expression of Dkk3 mRNA in schizophrenia was obtained (p < 0.012). Furthermore, using in situ hybridization, Dkk3 mRNA was shown to be abundantly expressed in cortical neurones, with prominent expression in layers II/III and V/VI of BA22. Dkk3 belongs to a novel family of Dkk proteins, which have been shown to be potent inhibitors of the neurodevelopmental wingless (Wnt) signalling pathway, and is therefore a putative candidate for further investigation into the aetiology of schizophrenia.
Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College London, Charing Cross Hospital, London, UK.
Saoussen
S
Ftouh
Mohammed T
MT
Akbar
Steven R
SR
Hirsch
Jacqueline S
JS
de Belleroche
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001345:Autoradiography / Q000379:methods; D015152:Blotting, Northern / Q000379:methods; D016022:Case-Control Studies; D018925:Chemokines; D003001:Cloning, Molecular / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D017403:In Situ Hybridization / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009693:Nucleic Acid Hybridization / Q000379:methods; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012559:Schizophrenia / Q000378:metabolism*; D017422:Sequence Analysis, DNA / Q000379:methods; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D013702:Temporal Lobe / Q000378:metabolism; D051153:Wnt Proteins
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D051153:Wnt Proteins