Developmental expression profile of quaking, a candidate gene for schizophrenia, and its target genes in human prefrontal cortex and hippocampus shows regional specificity

Abstract

Decreased expression of oligodendrocyte/myelin-related (OMR) genes, including quaking (QKI), is a consistent finding in gene expression studies of post-mortem brain from subjects with schizophrenia, and these changes are most prominent in the hippocampus vs. the prefrontal cortex (PFC). Although expression of QKI and other OMR genes has been examined in rodents, little is known about their developmental trajectory in the human brain. Therefore, we examined expression of QKI and several putative mRNA targets of QKI in human PFC and hippocampus at different ages. The pattern of QKI expression in the PFC resembled that reported in rodents, with high QKI-5 in the fetal brain and an increase in QKI-6 and QKI-7 during the period of active myelination, although QKI-5 expression did not decrease substantially during postnatal development in the PFC in humans as it does in rodent brain. Most of the putative QKI target genes also showed linear increases in expression with increasing age in the PFC. In contrast, expression of these genes showed little evidence of developmental regulation in the hippocampus. Correlations between expression levels of the nuclear vs. cytoplasmic QKI isoforms, and putative splicing targets of the former, also differed between tissues. Thus, we speculate that a robust increase in OMR gene expression normally occurs with age in the PFC, but not in the hippocampus, which may explain why decreases in OMR gene expression in schizophrenia are more pronounced in the latter tissue. We also suggest that OMR transcripts might be processed by different splicing proteins in different tissues.

Identification of epigenetic signature associated with alpha thalassemia/mental retardation X-linked syndrome

“…Many of the genes are involved in transcriptional regulation: PRDM9 encodes a histone H3 lysine-4 trimethyltransferase [23]; CTDP1 functions in recruiting RNA polymerase to DNA promoters and is an OMIM gene for congenital cataracts, facial dysmorphism and neuropathy [24]; TFB2M regulates mtDNA transcription and maintenance [25]; also ZNF300, ZNF274 and ATF7IP2 are transcriptional regulators [26–28]. Another gene, QKI , regulates RNA splicing, export of target RNAs from the nucleus, translation of proteins and RNA stability [29]. In addition, three genes encode proteins associated with methylation process, including the histone H3 lysine-4 trimethyltransferase, a known target of ATRX and the betaine–homocysteine methyltransferase 2-BHMT2, which catalyzes the methylation of homocysteine.…”

Convergence and Divergence in the Etiology of Myelin Impairment in Psychiatric Disorders and Drug Addiction

“…Importantly, the above risk genes are key regulators for various functional cascades. For instance, NGR1 and erbB receptors are known to activate a number of signaling pathways crucial for myelin formation [20,85,103]; SOX10 and Olig2 trigger the transcription cascade that supports OL fate specification and OL lineage development [13,104,105]; and QKI controls the posttranscriptional homeostasis of numerous mRNA ligands [45,51,106] to advance OL maturation and myelinogenesis [52,55]. Hence, a modest reduction of these risk genes may lead to a broad molecular consequence, which is a plausible possibility for myelin vulnerability.…”

“…One example is the selective RNA-binding protein QKI (Fig. 2) [45,47,[49][50][51]. Although the functional importance of QKI in human OLs has not been directly demonstrated, the essential roles of QKI in advancing OL development and myelination in animals are well-established [52][53][54][55].…”

Linkage and whole genome sequencing identify a locus on 6q25–26 for formal thought disorder and implicate MEF2A regulation

“…QKI encodes an RNA-binding protein that regulates pre-mRNA splicing, which is important in myelinisation and oligodendrocyte differentiation (Lauriat et al, 2008). The gene has been coupled to schizophrenia in a linkage-analysis of large Swedish pedigrees, which also found QKI down-regulated in post-mortem brains of patients with schizophrenia (Åberg et al, 2006;Lindholm et al, 2001).…”