Expression of the G72/G30 gene in transgenic mice induces behavioral changes

Abstract

The G72/G30 gene complex is a candidate gene for schizophrenia and bipolar disorder. However, G72 and G30 mRNAs are expressed at very low levels in human brain, with only rare splicing forms observed. We report here G72/G30 expression profiles and behavioral changes in a G72/G30 transgenic mouse model. A human BAC clone containing the G72/G30 genomic region was used to establish the transgenic mouse model, on which gene expression studies, Western blot and behavioral tests were performed. Relative to their minimal expression in humans, G72 and G30 mRNAs were highly expressed in the transgenic mice, and had a more complex splicing pattern. The highest G72 transcript levels were found in testis, followed by cerebral cortex, with very low or undetectable levels in other tissues. No LG72 (the long putative isoform of G72) protein was detected in the transgenic mice. Whole-genome expression profiling identified 361 genes differentially-expressed in transgenic mice compared to wild-type, including genes previously implicated in neurological and psychological disorders. Relative to wild-type mice, the transgenic mice exhibited fewer stereotypic movements in the open field test, higher baseline startle responses in the course of the prepulse inhibition test, and lower hedonic responses in the sucrose preference test. The transcriptome profile changes and multiple mouse behavioral effects suggest that the G72 gene may play a role in modulating behaviors relevant to psychiatric disorders.

Regulating levels of the neuromodulator d‐serine in human brain: structural insight into pLG72 and d‐amino acid oxidase interaction

“…With the same purpose, an even shorter protein form was designed: pLG72 1–94 . The latter variant lacks the last 59 residues which are conserved in the products of isoforms 1–3 of G72 gene transcript (GI:126362975, GI:240120173, GI:240120029, respectively) , and eventually correspond to the form of the human protein expressed in G72 transgenic mice, reported as AFB69504.1 in the NCBI database (GI:377551785) . The protein corresponding to pLG72 72–153 is recognized as an interaction domain with DAAO by the Pfam database (PF15199, http://pfam.xfam.org/): this observation suggests that it could correspond to a structurally and functionally stable domain.…”

Expression of D-Amino Acid Oxidase (DAO/DAAO) and D-Amino Acid Oxidase Activator (DAOA/G72) during Development and Aging in the Human Post-mortem Brain

“…The software carries out a normalization of the gene of interest with multiple reference genes, ultimately producing calibrated normalized relative quantities of the gene of interest which was used to perform statistical analysis (Hellemans et al, 2007). To detect DAOA mRNA in human post-mortem brain, qRT-PCR was performed using several different primers for DAOA gene described by Benzel et al (2008), Cheng et al (2014), and pre-designed primers [QT00058863 (Qiagen), Hs.PT.58.555086 (IDT), 4331182 (Thermo Fisher Scientific), qHsaCEP0024792 (Bio-Rad)]. As a positive control, these primers were also tested on the cDNA prepared from human neuroblastoma cells (SK-N-SH and SH-SY5Y) overexpressing DAOA, and these primers detected DAOA mRNA in these cells, but not in the human post-mortem brain samples (data not shown).…”

Pre-clinical models of neurodevelopmental disorders: focus on the cerebellum

“…G72 expression is prominent in granular cells of the cerebellum, the hippocampus, the cortex and the olfactory bulb. Compared to controls, G72Tg mice had altered expression of proteins involved in myelin-related processes, oxidative stress and mitochondrial function in the cerebellum, indicating the potential molecular correlates of schizophrenia-like behavior (Otte et al, 2009; Filiou et al, 2012; Cheng et al, 2013). Interestingly, an oral treatment with N-acetyl cysteine, a precursor of glutathione, increased the antioxidant capacity and rescued the spatial learning deficit in G72Tg mice (Otte et al, 2011).…”