Prefrontal cortex VAMP1 gene network moderates the effect of the early environment on cognitive flexibility in children.

During development, genetic and environmental factors interact to modify specific phenotypes. Both in humans and in animal models, early adversities influence cognitive flexibility, an important brain function related to behavioral adaptation to variations in the environment. Abnormalities in cognitive functions are related to changes in synaptic connectivity in the prefrontal cortex (PFC), and altered levels of synaptic proteins. We investigated if individual variations in the expression of a network of genes co-expressed with the synaptic protein VAMP1 in the prefrontal cortex moderate the effect of early environmental quality on the performance of children in cognitive flexibility tasks. Genes overexpressed in early childhood and co-expressed with the VAMP1 gene in the PFC were selected for study. SNPs from these genes (post-clumping) were compiled in an expression-based polygenic score (PFC-ePRS-VAMP1). We evaluated cognitive performance of the 4 years-old children in two cohorts using similar cognitive flexibility tasks. In the first cohort (MAVAN) we utilized two CANTAB tasks: (a) the Intra-/Extra-dimensional Set Shift (IED) task, and (b) the Spatial Working Memory (SWM) task. In the second cohort, GUSTO, we used the Dimensional Change Card Sort (DCCS) task. The results show that in 4 years-old children, the PFC-ePRS-VAMP1 network moderates responsiveness to the effects of early adversities on the performance in attentional flexibility tests. The same result was observed for a spatial working memory task. Compared to attentional flexibility, reversal learning showed opposite effects of the environment, as moderated by the ePRS. A parallel ICA analysis was performed to identify relationships between whole-brain voxel based gray matter density and SNPs that comprise the PFC-ePRS-VAMP1. The early environment predicts differences in gray matter content in regions such as prefrontal and temporal cortices, significantly associated with a genetic component related to Wnt signaling pathways. Our data suggest that a network of genes co-expressed with VAMP1 in the PFC moderates the influence of early environment on cognitive function in children.

Integrated analysis of gene expression signatures associated with colon cancer from three datasets.

PURPOSE: The present study aimed to elucidate the pathogenesis of colon cancer and identify genes associated with tumor development. METHODS: Three datasets, two (GSE74602 and GSE44861) from the Gene Expression Omnibus database and RNA-Seq colon cancer data from The Cancer Genome Atlas data portal, were downloaded. These three datasets were grouped using a meta-analysis approach, and differentially expressed genes (DEGs) were identified between colon tumor samples and adjacent normal samples. Functional enrichment analysis and regulatory factor predication were performed for significant genes. Additionally, small-molecule drugs associated with colon cancer were predicted, and a prognostic risk model was constructed. RESULTS: There were 251 overlapping DEGs (135 up- and 116 downregulated) between cancer samples and control samples in the three datasets. The DEGs were mainly involved in protein transport and apoptotic and neurotrophin signaling pathways. A total of 70 small-molecule drugs were predicated to be associated with colon cancer. Additionally, in the miRNA-target regulatory network, we found that SLC44A1 can be targeted by hsa-miR-183, hsa-miR-206, and hsa-miR-147, while KLF13 can be regulated by hsa-miR-182, hsa-miR-206, and hsa-miR-153. Moreover, the results of the prognostic risk model showed that four genes (VAMP1, P2RX5, CACNB1, and CRY2) could divide the samples into high and low risk groups. CONCLUSION: SLC44A1 and KLF13 may be involved in tumorigenesis and the metastasis of colon cancer by miRNA regulation. In addition, a four-gene (VAMP1, P2RX5, CACNB1, and CRY2) expression signature may have prognostic and predictive value in colon cancer.

The role of synaptobrevin1/VAMP1 in Ca2+-triggered neurotransmitter release at the mouse neuromuscular junction.

Synaptobrevin (Syb)/vesicle-associated membrane protein (VAMP) is a small, integral membrane protein of synaptic vesicles. Two homologous isoforms of synaptobrevin, Syb1/VAMP1 and Syb2/VAMP2, exhibit distinct but partially overlapping patterns of expression in adult mammalian neurons: Syb1 is predominantly expressed in the spinal cord, especially in motor neurons and motor nerve terminals of the neuromuscular junction (NMJ), whereas Syb2 is primarily expressed in central synapses in the brain. Whereas many studies have focused on the function of Syb2 in the brain, few studies have examined the role of Syb1. Here we report that Syb1 plays a critical role in neuromuscular synaptic transmission. A null mutation of Syb1 resulting from a spontaneous, nonsense mutation in mice significantly impairs the function, but not the structure, of the NMJ. In particular, both spontaneous and evoked synaptic activities in Syb1 mutant mice are reduced significantly relative to control mice. Short-term synaptic plasticity in Syb1-deficient NMJs is markedly altered: paired-pulse facilitation is significantly enhanced, suggesting a reduction in the initial release probability of synaptic vesicles. Furthermore, Syb1-deficient NMJs display a pronounced asynchrony in neurotransmitter release. These impairments are not due to an alteration of the size of the readily releasable pool of vesicles, but are attributable to reduced sensitivity and cooperativity to calcium (Ca2+) due to the absence of Syb1. Our findings demonstrate that Syb1 plays an essential, non-redundant role in Ca2+-triggered vesicle exocytosis at the mouse NMJ.

An insertion of intracisternal A-particle retrotransposon in a novel member of the phosphoglycerate mutase family in the lew allele of mutant mice.

Intracisternal A-particle retrotransposons (IAPs) are known, moveable, retrovirus-like elements and are defective in envelope protein synthesis in the mouse genome. Insertion of IAP elements can either interupt or enhance gene function or expression. Using a mouse model called lethal wasting (lew), we recently identified the insertion of an IAP sequence in a gene, 9630033F20Rik, that contains domains involved in glycolysis. The expression pattern of the 9630033F20Rik gene between various normal and diseased tissues was determined by semi-quantitative RT-PCR. The effect of the insertion mutation in 9630033F20Rik on glycolysis in heart, muscle, and brain tissues was further investigated using oligonuleotide microarray analysis. Results indicated that the expression of 9630033F20Rik is ubiquitous and its signal is relatively higher in heart and brain tissues. The insertion caused the deletion of exon 5 and decreased expression of this gene in all the tissues studied in the lew mice. Changes in the expression levels of glycolytic genes mainly occured in muscle tissue, raising a possibility that 9630033F20Rik may function as one of the transcriptional regulators of glycolytic genes in skeletal muscle. However, considering the fact that a single nucleotide mutation in vesicle-associated membrane protein 1 (VAMP1) has been reported as the causal gene for the lew mouse, how much of an impact the IAP insertion in the lew mouse phenotype has on glycolytic genes compared to the effect from the VAMP1 mutation responsible for the lew mouse phenotype should be further investigated.