“…Defining the regulation of GABA receptor promoters is still at an early stage, but the basic transcriptional “machinery” for several subunits (α1,α2,α3,α4,α5,α6,β1,β3,γ2 and δ) has been described in several reports (Kang et al, 1994; Kim et al, 1997; Penschuck et al, 1997; Mu and Burt, 1999; McLean et al, 2000; Russek et al, 2000; Fuchs and Celepirovic, 2002; Ma et al, 2004; Urak et al, 2006). Interestingly, using a computational analyses, several potential common transcriptional factor(s) have been identified for the α subunits (Steiger and Russek, 2004).…”
Inter-relationships ordinarily exist between mRNA expression of GABAA subunits in the frontopolar cortex (FPC) of individuals that had died suddenly from causes other than suicide. However, these correlations were largely absent in persons that had died by suicide. In the present investigation, these findings were extended by examining GABAA receptor expression patterns (of controls and depressed individuals that died by suicide) in the orbital frontal cortex (OFC), hippocampus, amygdala. locus coeruleus (LC) and paraventricular nucleus (PVN), all of which have been implicated in either depression, anxiety or stress responsivity. Using QPCR analysis, we found that in controls the inter-relations between GABAA subunits varied across brain regions, being high in the hippocampus and amygdala, intermediate in the LC, and low in the OFC and PVN. The GABAA subunit inter-relations were markedly different in persons that died by suicide, being reduced in hippocampus and amygdala, stable in the LC, but more coordinated in the OFC and to some extent in the PVN. It seems that altered brain region-specific inhibitory signaling, stemming from altered GABAA subunit coordination, are associated with depression/suicide. Although, it is unknown whether GABAA subunit re-organization was specifically tied to depression, suicide, or the accompanying distress, these data show that the coordinated expression of this transcriptome does vary depending on brain region and is plastic.
“…Defining the regulation of GABA receptor promoters is still at an early stage, but the basic transcriptional “machinery” for several subunits (α1,α2,α3,α4,α5,α6,β1,β3,γ2 and δ) has been described in several reports (Kang et al, 1994; Kim et al, 1997; Penschuck et al, 1997; Mu and Burt, 1999; McLean et al, 2000; Russek et al, 2000; Fuchs and Celepirovic, 2002; Ma et al, 2004; Urak et al, 2006). Interestingly, using a computational analyses, several potential common transcriptional factor(s) have been identified for the α subunits (Steiger and Russek, 2004).…”
Inter-relationships ordinarily exist between mRNA expression of GABAA subunits in the frontopolar cortex (FPC) of individuals that had died suddenly from causes other than suicide. However, these correlations were largely absent in persons that had died by suicide. In the present investigation, these findings were extended by examining GABAA receptor expression patterns (of controls and depressed individuals that died by suicide) in the orbital frontal cortex (OFC), hippocampus, amygdala. locus coeruleus (LC) and paraventricular nucleus (PVN), all of which have been implicated in either depression, anxiety or stress responsivity. Using QPCR analysis, we found that in controls the inter-relations between GABAA subunits varied across brain regions, being high in the hippocampus and amygdala, intermediate in the LC, and low in the OFC and PVN. The GABAA subunit inter-relations were markedly different in persons that died by suicide, being reduced in hippocampus and amygdala, stable in the LC, but more coordinated in the OFC and to some extent in the PVN. It seems that altered brain region-specific inhibitory signaling, stemming from altered GABAA subunit coordination, are associated with depression/suicide. Although, it is unknown whether GABAA subunit re-organization was specifically tied to depression, suicide, or the accompanying distress, these data show that the coordinated expression of this transcriptome does vary depending on brain region and is plastic.
“…In the present study, we have detected two different transcripts of the cp27 gene in the odontoblast cell line OB1 by Northern blot analysis (data not shown). In other cases, one gene may contain several hitherto unidentified 5′ untranslated regions (Menon et al, 1995; Mu and Burt, 1999). To date, only two full-length mouse CP27 cDNA sequences have been reported (GenBank NM_011801 and BC_005589).…”
The cp27 gene is a highly conserved and unique gene with important roles related to craniofacial organogenesis. The present study is a first analysis of the CP27 promoter and its regulation. Here, we have cloned the promoter of the mouse cp27 gene, examined its transcriptional activity, and identified transcription factor binding sites in the proximal promoter region. Two major transcription start sites were mapped adjacent to exon 1. Promoter function analysis of the 5′ flanking region by progressive 5′ deletion mutations localized transcription repression elements between −1993 bp to −969 bp and several positive elements between −968 bp and the preferred transcription start site. EMSA and functional studies indicated two function-cooperative CCAAT boxes and identified the NF-Y transcription factor as the CCAAT activator controlling transactivation of the CP27 promoter. In addition, this study demonstrated that for its effective binding and function, NF-Y required not only the minimal DNA segment length identified by deletion studies, but also a defined nucleotide sequence in the distal 3′ flanking region of the CP27 proximal promoter CCAAT box. These results provide a basis for our understanding of the specific regulation of the cp27 gene in the NF-Y-mediated gene transcription network.
“…The Gabra3 5′ UTR, exons, and intron/exon splice sites were sequenced in B6, NZB, and R3 but no strain-specific SNPs were identified. The Gabra3 promoter region could not be sequenced due to a highly repetitive structure (Mu and Burt 1999). Fig.…”
Section: Resultsmentioning
confidence: 99%
“…We found no sequence variations among the three strains. However, the mouse Gabra3 promoter contains a region of 55 GA repeats that have been shown to have an enhancer function in Gabra3 expression (Mu and Burt 1999). As deletion of these GA repeats results in a significant reduction in Gabra3 expression in vitro, it is possible that NZB mice carry a mutation that disrupts the promoter region.…”
The Tail Suspension Test (TST), which measures behavioral despair, is widely used as an animal model of human depressive disorders and antidepressant efficacy. In order to identify novel genes involved in the regulation of TST performance, we crossed an inbred strain exhibiting low immobility in the TST (RIIIS/J) with two high-immobility strains (C57BL/6J and NZB/BlNJ) to create two distinct F2 hybrid populations. All F2 offspring (n = 655) were genotyped at high density with a panel of SNP markers. Whole-genome interval mapping of the F2 populations identified statistically significant quantitative trait loci (QTLs) on mouse chromosomes (MMU) 4, 6, and X. Microarray analysis of hippocampal gene expression in the three parental strains was used to identify potential candidate genes within the MMUX QTLs identified in the NZB/BlNJ × RIIIS/J cross. Expression of Gabra3, which encodes the GABAA receptor α3 subunit, was robust in the hippocampus of B6 and RIIIS mice but absent from NZB hippocampal tissue. To verify the role of Gabra3 in regulating TST behavior in vivo, mice were treated with SB-205384, a positive modulator of the α3 subunit. SB-205384 significantly reduced TST immobility in B6 mice without affecting general activity, but it had no effect on behavior in NZB mice. This work suggests that GABRA3 regulates a behavioral endophenotype of depression and establishes this gene as a viable new target for the study and treatment of human depression.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-010-9266-6) contains supplementary material, which is available to authorized users.
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