Disease relevance of Gad1

• We show that these sites specifically bind to Pitx2 protein in vitro and that in transfected neuroblastoma cells, the Pitx2 binding sites contribute to the basal activity of the Gad1 promoter [1].
• Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase [2].
• The expression of both GAD 67 and GAD 65 genes specifically in islet beta-cells indicates that both GAD forms are candidate autoantigens in rodent models of insulin-dependent diabetes mellitus [3].
• Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse [4].
• Here, we constructed plasmid (amplicon) Herpes Simplex Virus (HSV-1) vectors that placed the Lac Z gene under the regulation of putative PAG, VGLUT1, or GAD67 promoters [5].

Psychiatry related information on Gad1

• Those containing glutamate decarboxylase terminate in the superficial dorsal horn and are likely to be involved in antinociception, whereas those containing peptides terminate principally in motor nuclei and are likely to modulate motor activity [6].

High impact information on Gad1

• Here we determine the temporal sequence of T-cell and antibody responses in NOD mice to a panel of five murine beta-cell antigens and find that antibody and T-cell responses specific for the two isoforms of glutamic acid decarboxylase (GAD) are first detected in 4-week-old NOD mice [7].
• Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice [7].
• Cytotoxic T cells specific for glutamic acid decarboxylase in autoimmune diabetes [8].
• Moreover, proliferating precursor cells did not generate other types of cerebellar neurons, as judged by the lack of expression of glutamic acid decarboxylase, the synthetic enzyme for gamma-amino-n-butyric acid [9].
• Based on morphologic criteria and the expression of glutamic acid decarboxylase, the newly generated Purkinje cells were functional [10].

Chemical compound and disease context of Gad1

• Glutamatergic or GABAergic neuron-specific, long-term expression in neocortical neurons from helper virus-free HSV-1 vectors containing the phosphate-activated glutaminase, vesicular glutamate transporter-1, or glutamic acid decarboxylase promoter [5].
• We report the transcriptional initiation sites and promoter sequences important for expression in islet beta-cells and C6 glioma cells, and demonstrate that the GAD67 promoter harbors elements that are responsive to glucose in primary islet cells [11].

Biological context of Gad1

• In addition, suggestive linkage is indicated for two loci on mouse chromosome 2, one near Gad1 encoding glutamic acid decarboxylase, and the other near the El2 locus which influences the seizure phenotype in the neurological mutant strain El [12].
• Valproic acid (2 mmolkg for 15 days, twice a day) reverted l-methionine-induced down-regulation of reelin and GAD67 in both WT and heterozygous reeler mice, suggesting an epigenetic action through the inhibition of histone deacetylases [13].
• The hydrophilic isoform of glutamate decarboxylase, GAD67, is targeted to membranes and nerve terminals independent of dimerization with the hydrophobic membrane-anchored isoform, GAD65 [14].
• Ontogeny of glutamic acid decarboxylase gene expression in the mouse pancreas [15].
• These findings suggest that DNA hypermethylation and the associated chromatin remodeling may be critically important in mediating the epigenetic down-regulation of reelin and GAD67 expression detected in cortical GABAergic interneurons of SZ patients [16].

Anatomical context of Gad1

• Building on these results we show that Gad1-lacZ "knockin" reporter ES cell lines can be used to easily monitor Gad1 expression patterns and expression levels during ES differentiation [17].
• The objective of this study was to define additional structures outside of the central nervous system that express Gad1, indicating those structures that may require its function for normal development [18].
• 5. Tissues expressing Gad1 included the tail bud mesenchyme, the pharyngeal pouches and arches, the ectodermal placodes of the developing vibrissae, and the apical ectodermal ridge (AER), mesenchyme and ectoderm of the limb buds [18].
• Reelin and glutamic acid decarboxylase (GAD)67 expressed by cortical gamma-aminobutyric acid-ergic interneurons are down-regulated in schizophrenia [13].
• GAD activities and GABA contents were reduced to 20% and 7%, respectively, in the cerebral cortex of the newborn GAD67 -/- mice [2].

Associations of Gad1 with chemical compounds

• Therefore, these results do not support the hypothesis of an involvement of Gad1 or Gad2 in the pathophysiology of acute ethanol withdrawal severity and the other ethanol related traits [19].
• The dynamic expression of Gad1 in such tissues suggests a wider role for GABA signaling in development than was previously appreciated [18].
• Protracted l-methionine (6.6 mmolkg for 15 days, twice a day) treatment in mice elicited in brain an increase of S-adenosyl-homocysteine, the processing product of the methyl donor S-adenosyl-methionine, and a marked decrease of reelin and GAD67 mRNAs in both WT and heterozygous reeler mice [13].
• Furthermore, in GAD65-/- mouse brain, GAD67, which no longer partitions into the Triton X-114 detergent phase, still anchors to membranes at similar levels as in wild-type mice [14].
• In brain extracts, almost all GAD67 is in an active holoenzyme form, saturated with its cofactor, pyridoxal phosphate [20].

Physical interactions of Gad1

• In these mice the histone deacetylase inhibitor valproate, which increases acetylated histone content in cortical GABAergic interneurons, also prevents MET-induced RELN promoter hypermethylation and reduces the methyl-CpG binding domain protein binding to RELN and GAD67 promoters [16].

Co-localisations of Gad1

• Cav2.1 staining was colocalized with staining for antibodies against glutamic acid decarboxylase and corresponded well with the pericellular network formed by GABAergic basket cell interneurons [21].

Regulatory relationships of Gad1

• These results indicate that Pitx2 may regulate Gad1 expression in mammals, suggesting a new role for this key developmental transcription factor as a regulator of GABAergic differentiation during mammalian neural development [1].
• Ectopic expression of the Dlx genes induces glutamic acid decarboxylase and Dlx expression [22].
• In addition, a subpopulation of cells positive for ErbB4 mRNA in postnatal cortex and striatum coexpressed mRNA for either EGFR or GAD67, a marker for gamma-aminobutyric acid (GABA)ergic interneurons, suggesting that both ErbB4 and EGFR are coexpressed in GABAergic interneurons [23].
• We now report that in these mice, RELN and GAD67 promoters express an increased recruitment of methyl-CpG binding domain proteins [16].
• Under these conditions, most cells (approximately 85%) express high levels of the cholinergic markers acetyl cholinesterase and choline acetyltransferase while approximately 10% of cells express the GABAergic marker glutamic acid decarboxylase [24].

Other interactions of Gad1

• GABA is synthesized by glutamic acid decarboxylase (GAD), but the respective roles of its two isoforms (GAD65 and 67) have not been determined [2].
• More importantly, the Dnmt1 knockdown blocked the methionine-induced reelin and GAD67 mRNA down-regulation [25].
• Hypermethlyation of RELN and GAD67 promoters can be induced by treating mice with methionine, and these mice display brain and behavioral abnormalities similar to +/rl [26].
• We have administered methionine (2 mM) to primary cultures of cortical neurons prepared from embryonic day 16 mice and show that this treatment down-regulated reelin and glutamic acid decarboxylase 67 (GAD67) mRNA expression but not that corresponding to neuron-specific enolase mRNA [25].
• Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase [27].

Analytical, diagnostic and therapeutic context of Gad1

• GAD 67 mRNA was more abundant than GAD 65, and both were localized to islet beta-cells by in situ hybridization [3].
• We studied the expression of GABA, glutamate decarboxylase 65 (GAD65) and GAD67 by immunocytochemistry and Western blot, in the retinas of control and dark-reared C57BL/6J black mice [28].
• Western blot analysis showed corresponding differences in the levels of GAD65 but not of GAD67 expression between control and dark-rearing conditions [28].
• Using two RT-PCR quantitative assays, we measured the pancreatic expression of the two isoforms of glutamic acid decarboxylase in the foetus, newborn and 14-, 21- and 35-day-old male and female NOD and C57BL/6 mice [15].
• Pancreatic hormone and glutamic acid decarboxylase expression in the mouse thymus: a real-time PCR study [29].

References