Brain-specific Angiogenesis Inhibitor 1-associated Protein Research Articles

Hippocampal BAIAP2 prevents chronic mild stress-induced depression-like behaviors in mice.

The pathogenesis of depression is closely related to changes in hippocampal synaptic plasticity; however, the underlying mechanism is still unclear. Brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2), a postsynaptic scaffold protein in excitatory synapses important for synaptic plasticity, is highly expressed in the hippocampus and has been implicated in several psychiatric disorders. However, the role of BAIAP2 in depression remains poorly understood. In the present study, a mouse model of depression was established via exposure to chronic mild stress (CMS). An adeno-associated virus (AAV) vector expressing BAIAP2 was injected into the hippocampal brain region of mice and a BAIAP2 overexpression plasmid was transfected into HT22 cells to upregulate BAIAP2 expression. Depression- and anxiety-like behaviors and dendritic spine density were examined in mice using behavioral tests and Golgi staining, respectively. In vitro, hippocampal HT22 cells were treated with corticosterone (CORT) to simulate the stress state, and the effect of BAIAP2 on CORT-induced cell injury was explored. Reverse transcription-quantitative PCR and western blotting were employed to determine the expression levels of BAIAP2 and those of the synaptic plasticity-related proteins glutamate receptor ionotropic, AMPA 1 (GluA1), and synapsin 1 (SYN1). Mice exposed to CMS exhibited depression- and anxiety-like behaviors accompanied by decreased levels of BAIAP2 in the hippocampus. In vitro, the overexpression of BAIAP2 increased the survival rate of CORT-treated HT22 cells and upregulated the expression of GluA1 and SYN1. Consistent with the in vitro data, the AAV-mediated overexpression of BAIAP2 in the hippocampus of mice significantly inhibited CMS-induced depression-like behavior, concomitant with increases in dendritic spine density and the expression of GluA1 and SYN1 in hippocampal regions. Our findings indicate that hippocampal BAIAP2 can prevent stress-induced depression-like behavior and may be a promising target for the treatment of depression or other stress-related diseases.

Identification of TRAPPC9 and BAIAP2 Gene Polymorphisms and Their Association With Fat Deposition-Related Traits in Hu Sheep.

Fat deposition is an important economic trait that is closely related to feed efficiency and carcass performance in livestock. In this study, the fat deposition-related traits of 1,293 Hu sheep were measured and descriptive statistical analysis was conducted. The results showed that the coefficient of variation of all fat deposition-related traits was higher than 24%. In addition, single nucleotide polymorphisms and the expression characteristics of TRAPPC9 (encoding trafficking protein particle complex subunit 9) and BAIAP2 (encoding brain-specific Angiogenesis inhibitor 1-associated protein 2) genes in Hu sheep were detected using PCR amplification, Sanger sequencing, KASPar genotyping, and quantitative real-time reverse transcription PCR (qRT-PCR). The associations between SNPs and fat deposition-related traits were also analyzed. Two intronic mutations, TRAPPC9 g.57654 A > G and BAIAP2 g.46061 C > T, were identified in Hu sheep. The result of association analysis showed that TRAPPC9 g.57654 A > G and BAIAP2 g.46061 C > T were both significantly associated with the weight of tail fat, tail fat relative weight (body weight), and tail fat relative weight (carcass) (P < 0.05). Comprehensive effects analysis showed that there were significant differences between the combined genotypes and tail fat and perirenal fat deposition. Moreover, qRT-PCR analysis showed that TRAPPC9 and BAIAP2 are widely expressed, and their expression levels were significantly higher in the small-tail group compared with those in the big-tail group (P < 0.01). These results provided important candidate molecular markers that could be used in strategies to reduce tail fat deposition in Hu sheep.

Ca2+ entry through mechanotransduction channels localizes BAIAP2L2 to stereocilia tips.

Brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 2 (BAIAP2L2), a membrane-binding protein required for the maintenance of mechanotransduction in hair cells, is selectively retained at the tips of transducing stereocilia. BAIAP2L2 trafficked to stereocilia tips in the absence of EPS8, but EPS8 increased the efficiency of localization. A tripartite complex of BAIAP2L2, EPS8, and MYO15A formed efficiently in vitro, and these three proteins robustly targeted to filopodia tips when coexpressed in cultured cells. Mice lacking functional transduction channels no longer concentrated BAIAP2L2 at row 2 stereocilia tips, a result that was phenocopied by blocking channels with tubocurarine in cochlear explants. Transduction channels permit Ca2+ entry into stereocilia, and we found that membrane localization of BAIAP2L2 was enhanced in the presence of Ca2+. Finally, reduction of intracellular Ca2+ in hair cells using BAPTA-AM led to a loss of BAIAP2L2 at stereocilia tips. Taken together, our results show that a MYO15A-EPS8 complex transports BAIAP2L2 to stereocilia tips, and Ca2+ entry through open channels at row 2 tips retains BAIAP2L2 there.

Baiap3 regulates depressive behaviors in mice via attenuating dense core vesicle trafficking in subsets of prefrontal cortex neurons

Selective serotonin reuptake inhibitors (SSRIs) are effective first line therapies for treating depression, but are plagued by undesirable side effects and are not effective in all patients. Because SSRIs effectively deplete the neuronal releasable serotonin (5-HT) pool, gaining a deeper understanding of intracellular mechanisms regulating 5-HT pools can help us understand the shortcomings of SSRIs and develop more effective therapies. In this study, we found that BAIAP3 (brain-specific angiogenesis inhibitor 1-associated protein 3) is significantly downregulated in two mouse models of depression (the IR- and CUMS-induced depressive mouse models). In BAIAP3 downregulated models (in vitro and in vivo), we discovered that trafficking of dense core vesicle (DCV), organelles that store, transport and release cargo via exocytosis, was reduced. Accordingly, 5-HT exocytosis and levels in the synapse were lowered, causing defective post-synaptic neurotransmission. In a screen of natural products, we identified eucalyptol, the active components of Eucalyptus, as uniquely capable of increasing neuronal Baiap3 expression and elevate synaptic 5-HT levels. Moreover, eucalyptol treatment relieved depressive behavioral symptoms and restored serotonin levels in mice. Mechanistically, eucalyptol restores Baiap3 expression by reducing inhibitory microRNAs (miR-329, miR-362). These findings illuminate how Baiap3 depletion propagates neurotransmission dysfunction and point to eucalyptol as a novel agent for restoring serotonin exocytosis, suggesting potential for developing eucalyptol as a therapy for treating depression.

BAIAP2L2 facilitates the malignancy of prostate cancer (PCa) via VEGF and apoptosis signaling pathways.

Prostate cancer (PCa) is the second most common type of male cancer in western. Despite key roles of brain-specific angiogenesis inhibitor 1-associated protein like 2 (BAIAP2L2) in several cancers, the function of BAIAP2L2 in PCa is never reported. We aimed to investigate the role of BAIAP2L2 in the progression of PCa and decipher the underlying mechanisms. RNA sequencing data from TCGA database were used to evaluate the expression of BAIAP2L2 in PCa. Survival analysis and Cox regression model analysis were conducted to evaluate the prognostic value of BAIAP2L2. BAIAP2L2-associated pathways were preliminary analyzed by Gene Set Enrichment Analysis (GSEA) method and confirmed by western blot assays. Cell proliferation and transwell assays were performed to determine biological behaviors in BAIAP2L2 knocked-down or overexpressed PCa cell lines including LNCaP and PC-3 cells. In our study, BAIAP2L2 was significantly up-regulated in PCa tissues and cell lines and independently associated with the poor prognosis of PCa patients. Knockdown of BAIAP2L2 notably repressed proliferation, migration and invasion of PCa cells. And overexpression of BAIAP2L2 obtained the contrary results. Mechanically, GSEA method and western blot results of key molecules in signaling pathways implicated that the depletion of BAIAP2L2 inactivated the vascular endothelial growth factors (VEGFs) and induced apoptosis signaling pathways in PCa cells. Overall, these findings revealed that BAIAP2L2 may support tumorigenesis and malignant development of prostate cancer cells via VEGF and apoptosis signaling pathways, and it could be considered as a promising biomarker and independent prognostic predictor of prostate cancer.

Label-free proteomics differences in the dorsolateral prefrontal cortex between bipolar disorder patients with and without psychosis

BackgroundPsychosis is common in bipolar disorder (BD) and is related to more severe cognitive impairments. Since the molecular mechanism of BD psychosis is elusive, we conducted this study to explore the proteomic differences associated with BD psychosis in the dorsolateral prefrontal cortex (DLPFC; BA9). MethodsPostmortem DLPFC gray matter tissues from five pairs of age-matched male BD subjects with and without psychosis history were used. Tissue proteomes were identified and quantified by label-free liquid chromatography tandem mass spectrometry and then compared between groups. Statistical significance was set at q < 0.40 and Log2 fold change (Log2FC) ≥ |1|. Protein groups with differential expression between groups at p < 0.05 were subjected to pathway analysis. ResultsEleven protein groups differed significantly between groups, including the reduction of tenascin C (q = 0.005, Log2FC = −1.78), the elevations of synaptoporin (q = 0.235, Log2FC = 1.17) and brain-specific angiogenesis inhibitor 1-associated protein 3 (q = 0.241, Log2FC = 2.10) in BD with psychosis. The between-group differences of these proteins were confirmed by Western blots. The top enriched pathways (p < 0.05 with ≥ 3 hits) were the outgrowth of neurons, neuronal cell proliferation, growth of neurites, and outgrowth of neurites, which were all predicted to be upregulated in BD with psychosis. LimitationsSmall sample size and uncertain relationships of the observed proteomic differences with illness stage and acute psychosis. ConclusionsThese results suggested BD with psychosis history may be associated with abnormalities in neurodevelopment, neuroplasticity, neurotransmission, and neuromodulation in the DLPFC.

Effect of the miR-96-5p inhibitor and mimic on the migration and invasion of the SW480-7 colorectal cancer cell line.

The objectives of the present study were to identify the aberrant expression of microRNA (miRNA) in colorectal carcinoma (CRC) tissues from published miRNA profiling studies and to investigate the effects of the identified miRNA inhibitor and mimic miR-96-5p on CRC cell migration and invasion. The altered expression of the regulators of cytoskeleton mRNA in miR-96-5p inhibitor-transfected cells was determined. The miR-96-5p expression level in five CRC cell lines, HCT11, CaCo2, HT29, SW480 and SW620, and 26 archived paraffin-embedded CRC tissues were also investigated by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR). Cell viability in response to the miR-96-5p inhibitor and mimic transfections was determined by an MTT assay. A Matrigel invasion assay was conducted to select the invasive subpopulation designated SW480-7, by using the parental cell line SW480. The effects of miR-96-5p mimic- or inhibitor-transfected SW480-7 cells on cell migration and invasion were evaluated using the Transwell and Matrigel assays, and the change in expression of the regulators of cytoskeleton mRNAs was identified by Cytoskeleton Regulators RT2-Profiler PCR array followed by validation with RT-qPCR. CRC tissues exhibited a significant increase in miR-96-5p expression, compared with their matched normal adjacent tissues, indicating an oncogenic role for miR-96-5p. The results demonstrated that the miR-96-5p inhibitor decreased the migration of SW480-7 cells, but had no effect on invasion. This may be due to the promotion of cell invasion by Matrigel, which counteracts the blockade of cell invasion by the miR-96-5p inhibitor. The miR-96-5p mimic enhanced SW480-7 cell migration and invasion, as expected. It was determined that there was a >2.5 fold increase in the expression of genes involved in cytoskeleton regulation, myosin light chain kinase 2, pleckstrin homology like domain family B member 2, cyclin A1, IQ motif containing GTPase activating protein 2, Brain-specific angiogenesisinhibitor 1-associated protein 2 and microtubule-actin crosslinking factor 1, in miR-96-5p inhibitor-transfected cells, indicating that they are negative regulators of cell migration. In conclusion, the miR-96-5p inhibitor blocked cell migration but not invasion, and the latter may be due to the counteraction of Matrigel, which has been demonstrated to stimulate cell invasion.

A survey of microRNA single nucleotide polymorphisms identifies novel breast cancer susceptibility loci in a case-control, population-based study of African-American women

BackgroundMicroRNAs (miRNAs) regulate gene expression and influence cancer. Primary transcripts of miRNAs (pri-miRNAs) are poorly annotated and little is known about the role of germline variation in miRNA genes and breast cancer (BC). We sought to identify germline miRNA variants associated with BC risk and tumor subtype among African-American (AA) women.MethodsUnder the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, genotyping and imputed data from four studies on BC in AA women were combined into a final dataset containing 224,188 miRNA gene single nucleotide polymorphisms (SNPs) for 8350 women: 3663 cases and 4687 controls. The primary miRNA sequence was identified for 566 miRNA genes expressed in Encyclopedia of DNA Elements (ENCODE) Tier 1 cell types and human pancreatic islets. Association analysis was conducted using logistic regression for BC status overall and by tumor subtype.ResultsA novel BC signal was localized to an 8.6-kb region of 17q25.3 by four SNPs (rs9913477, rs1428882938, rs28585511, and rs7502931) and remained statistically significant after multiple test correction (odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.26–1.65; p = 3.15 × 10−7; false discovery rate (FDR) = 0.03). These SNPs reside in a genomic location that includes both the predicted primary transcript of the noncoding miRNA gene MIR3065 and the first intron of the gene for brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2). Furthermore, miRNA-associated SNPs on chromosomes 1p32.3, 5q32, and 3p25.1 were the strongest signals for hormone receptor, luminal versus basal-like, and HER2 enrichment status, respectively. A second phase of genotyping (1397 BC cases, 2418 controls) that included two SNPs in the 8.6-kb region was used for validation and meta-analysis. While neither rs4969239 nor rs9913477 was validated, when meta-analyzed with the original dataset their association with BC remained directionally consistent (OR = 1.29, 95% CI = 1.16–1.44 (p = 4.18 × 10–6) and OR = 1.33, 95% CI = 1.17–1.51 (p = 1.6 × 10–5), respectively).ConclusionGermline genetic variation indicates that MIR3065 may play an important role in BC development and heterogeneity among AA women. Further investigation to determine the potential functional effects of these SNPs is warranted. This study contributes to our understanding of BC risk in AA women and highlights the complexity in evaluating variation in gene-dense regions of the human genome.

Inter-hemispherical asymmetry in default-mode functional connectivity and BAIAP2 gene are associated with anger expression in ADHD adults

Attention deficit hyperactivity disorder (ADHD) is accompanied by resting-state alterations, including abnormal activity, connectivity and asymmetry of the default-mode network (DMN). Concurrently, recent studies suggested a link between ADHD and the presence of polymorphisms within the gene BAIAP2 (i.e., brain-specific angiogenesis inhibitor 1-associated protein 2), known to be differentially expressed in brain hemispheres. The clinical and neuroimaging correlates of this polymorphism are still unknown. We investigated the association between BAIAP2 polymorphisms and DMN functional connectivity (FC) asymmetry as well as behavioral measures in ADHD adults. Resting-state fMRI was acquired from 30 ADHD and 15 healthy adults. For each subject, rs7210438 and rs8079626 within the gene BAIAP2 were genotyped. ADHD severity, impulsiveness and anger were assessed for the ADHD group. Using multivariate analysis of variance, we found that genetic features do have an impact on DMN FC asymmetry. In particular, polymorphism rs8079626 affects medial frontal gyrus and inferior parietal lobule connectivity asymmetry, lower for AA than AG/GG carriers. Further, when combining FC asymmetry and the presence of the rs8079626 variant, we successfully predicted increased externalization of anger in ADHD. In conclusion, a complex interplay between genetic vulnerability and inter-hemispherical DMN FC asymmetry plays a role in emotion regulation in adult ADHD.

Identification of protein biomarkers of mercury toxicity in fish

Bioaccumulative metals such as mercury are found in increasing amounts in fish and their consumers. In the region of the Madeira River, in the Brazilian Amazon, mercury (Hg) is a predominant contaminant in the aquatic ecosystem. There is therefore a need to find specific biomarkers of mercury toxicity in fish to monitor contaminations. Here, mercury-bound proteins were identified in the liver tissues of fishes Mylossoma duriventre and Brachyplatystoma rousseauxii. Mercury was quantified in liver tissue, pellets and protein spots by graphite furnace atomic absorption. Proteins were fractionated by two-dimensional polyacrylamide gel electrophoresis and identified by mass spectrometry with electrospray ionization. We identified nine proteins linked to mercury and that presented biomarker characteristics of mercury. Among the proteins identified, isoforms of parvalbumin, ubiquitin-40S ribosomal protein S27a, brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 2 and betaine–homocysteine S-methyltransferase 1 are notable for having the molecular function of binding to metallic ions.

DNA methylation as a putative mechanism for reduced dendritic spine density in the superior temporal gyrus of subjects with schizophrenia

Reduced dendritic spine density (DSD) in cortical layer 3 of the superior temporal gyrus (STG), and multiple other brain regions, is consistently observed in postmortem studies of schizophrenia (SZ). Elucidating the molecular mechanisms of this intermediate phenotype holds promise for understanding SZ pathophysiology, identifying SZ treatment targets and developing animal models. DNA methylation (DNAm), the addition of a methyl group to a cytosine nucleotide, regulates gene transcription and is a strong candidate for such a mechanism. We tested the hypothesis that DNAm correlates with DSD in the human STG and that this relationship is disrupted in SZ. We used the Illumina Infinium HumanMethylation450 Beadchip Array to quantify DNAm on a genome-wide scale in the postmortem STG from 22 SZ subjects and matched non-psychiatric control (NPC) subjects; DSD measures were available for 17 of the 22 subject pairs. We found DNAm to correlate with DSD at more sites than expected by chance in NPC, but not SZ, subjects. In addition, we show that the slopes of the linear DNAm-DSD correlations differed between SZ and NPC subjects at more sites than expected by chance. From these data, we identified 2 candidate genes for mediating DSD abnormalities in SZ: brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) and discs large, Drosophila, homolog of, 1 (DLG1). Together, these data suggest that altered DNAm in SZ may be a mechanism for SZ-related DSD reductions.

Attention-deficit hyperactivity disorder in adults: a systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies.

The adult form of attention-deficit/hyperactivity disorder has a prevalence of up to 5% and is the most severe long-term outcome of this common disorder. Family studies in clinical samples as well as twin studies suggest a familial liability and consequently different genes were investigated in association studies. Pharmacotherapy with methylphenidate (MPH) seems to be the first-line treatment of choice in adults with attention-deficit hyperactive disorder (ADHD) and some studies were conducted on the genes influencing the response to this drug. Finally some peripheral biomarkers were identified in ADHD adult patients. We believe this work is the first systematic review and meta-analysis of candidate gene association studies, pharmacogenetic and biochemical (metabolomics) studies performed in adults with ADHD to identify potential genetic, predictive and peripheral markers linked specifically to ADHD in adults. After screening 5129 records, we selected 87 studies of which 61 were available for candidate gene association studies, 5 for pharmacogenetics and 21 for biochemical studies. Of these, 15 genetic, 2 pharmacogenetic and 6 biochemical studies were included in the meta-analyses. We obtained an association between adult ADHD and the gene BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2), even after Bonferroni correction, with any heterogeneity in effect size and no publication bias. If we did not apply the Bonferroni correction, a trend was found for the carriers allele 9R of dopamine transporter SLC6A3 40 bp variable tandem repeat polymorphism (VNTR) and for 6/6 homozygotes of SLC6A3 30 bp VNTR. Negative results were obtained for the 9-6 haplotype, the dopamine receptor DRD4 48 bp VNTR, and the enzyme COMT SNP rs4680. Concerning pharmacogenetic studies, no association was found for the SLC6A3 40 bp and response to MPH with only two studies selected. For the metabolomics studies, no differences between ADHD adults and controls were found for salivary cortisol, whereas lower serum docosahexaenoic acid (DHA) levels were found in ADHD adults. This last association was significant even after Bonferroni correction and in absence of heterogeneity. Other polyunsaturated fatty acids (PUFAs) such as AA (arachidonic acid), EPA (eicosapentaenoic acid) and DyLA (dihomogammalinolenic acid) levels were not different between patients and controls. No publication biases were observed for these markers. Genes linked to dopaminergic, serotoninergic and noradrenergic signaling, metabolism (DBH, TPH1, TPH2, DDC, MAOA, MAOB, BCHE and TH), neurodevelopment (BDNF and others), the SNARE system and other forty genes/proteins related to different pathways were not meta-analyzed due to insufficient data. In conclusion, we found that there were not enough genetic, pharmacogenetic and biochemical studies of ADHD in adults and that more investigations are needed. Moreover we confirmed a significant role of BAIAP2 and DHA in the etiology of ADHD exclusively in adults. Future research should be focused on the replication of these findings and to assess their specificity for ADHD.

Attention-deficit hyperactivity disorder in adults: A systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies.

The adult form of attention-deficit/hyperactivity disorder has a prevalence of up to 5% and is the most severe long-term outcome of this common disorder. Family studies in clinical samples as well as twin studies suggest a familial liability and consequently different genes were investigated in association studies. Pharmacotherapy with methylphenidate (MPH) seems to be the first-line treatment of choice in adults with attention-deficit hyperactive disorder (ADHD) and some studies were conducted on the genes influencing the response to this drug. Finally some peripheral biomarkers were identified in ADHD adult patients. We believe this work is the first systematic review and meta-analysis of candidate gene association studies, pharmacogenetic and biochemical (metabolomics) studies performed in adults with ADHD to identify potential genetic, predictive and peripheral markers linked specifically to ADHD in adults. After screening 5129 records, we selected 87 studies of which 61 were available for candidate gene association studies, 5 for pharmacogenetics and 21 for biochemical studies. Of these, 15 genetic, 2 pharmacogenetic and 6 biochemical studies were included in the meta-analyses. We obtained an association between adult ADHD and the gene BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2), even after Bonferroni correction, with any heterogeneity in effect size and no publication bias. If we did not apply the Bonferroni correction, a trend was found for the carriers allele 9R of dopamine transporter SLC6A3 40 bp variable tandem repeat polymorphism (VNTR) and for 6/6 homozygotes of SLC6A3 30 bp VNTR. Negative results were obtained for the 9-6 haplotype, the dopamine receptor DRD4 48 bp VNTR, and the enzyme COMT SNP rs4680. Concerning pharmacogenetic studies, no association was found for the SLC6A3 40 bp and response to MPH with only two studies selected. For the metabolomics studies, no differences between ADHD adults and controls were found for salivary cortisol, whereas lower serum docosahexaenoic acid (DHA) levels were found in ADHD adults. This last association was significant even after Bonferroni correction and in absence of heterogeneity. Other polyunsaturated fatty acids (PUFAs) such as AA (arachidonic acid), EPA (eicosapentaenoic acid) and DyLA (dihomogammalinolenic acid) levels were not different between patients and controls. No publication biases were observed for these markers. Genes linked to dopaminergic, serotoninergic and noradrenergic signaling, metabolism (DBH, TPH1, TPH2, DDC, MAOA, MAOB, BCHE and TH), neurodevelopment (BDNF and others), the SNARE system and other forty genes/proteins related to different pathways were not meta-analyzed due to insufficient data. In conclusion, we found that there were not enough genetic, pharmacogenetic and biochemical studies of ADHD in adults and that more investigations are needed. Moreover we confirmed a significant role of BAIAP2 and DHA in the etiology of ADHD exclusively in adults. Future research should be focused on the replication of these findings and to assess their specificity for ADHD.

BAIAP2 Is Related to Emotional Modulation of Human Memory Strength

Memory performance is the result of many distinct mental processes, such as memory encoding, forgetting, and modulation of memory strength by emotional arousal. These processes, which are subserved by partly distinct molecular profiles, are not always amenable to direct observation. Therefore, computational models can be used to make inferences about specific mental processes and to study their genetic underpinnings. Here we combined a computational model-based analysis of memory-related processes with high density genetic information derived from a genome-wide study in healthy young adults. After identifying the best-fitting model for a verbal memory task and estimating the best-fitting individual cognitive parameters, we found a common variant in the gene encoding the brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) that was related to the model parameter reflecting modulation of verbal memory strength by negative valence. We also observed an association between the same genetic variant and a similar emotional modulation phenotype in a different population performing a picture memory task. Furthermore, using functional neuroimaging we found robust genotype-dependent differences in activity of the parahippocampal cortex that were specifically related to successful memory encoding of negative versus neutral information. Finally, we analyzed cortical gene expression data of 193 deceased subjects and detected significant BAIAP2 genotype-dependent differences in BAIAP2 mRNA levels. Our findings suggest that model-based dissociation of specific cognitive parameters can improve the understanding of genetic underpinnings of human learning and memory.

Insulin receptor, IRS1, IRS2, INSIG1, INSIG2, RRAD, and BAIAP2 gene expressions in glioma U87 cells with ERN1 loss of function: effect of hypoxia and glutamine or glucose deprivation

The purpose of this study was to examine: 1) the association between the expression of the insulin receptor (INSR), insulin receptor substrate 1 (IRS1) and 2 (IRS2), insulin inducible gene 1 (INSIG1) and 2 (INSIG2), Ras-related associated with diabetes (RRAD), and brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) genes in glioma cells and 2) the function of the endoplasmic reticulum stress signaling, mediated by endoplasmic reticulum to nuclei-1 (ERN1) and regulation of these gene expressions by hypoxia and glucose or glutamine deprivation. The expression of the INSR, IRS1, IRS2, INSIG1, INSIG2, RRAD, and BAIAP2 genes in the glioma cell line U87 and its subline with ERN1 loss of function was studied by qPCR. The cells were exposed to a mix of 3 % oxygen and 5 % carbon dioxide and glucose or glutamine deprivation. The blockade of the ERN1 signaling enzyme function in glioma cells leads to the gene expression increase in INSR, INSIG2, and IRS2 and decrease in the BAIAP2 and RRAD genes. Hypoxia affected the expression of the INSR, IRS1, IRS2, INSIG1, INSIG2, and BAIAP2 genes with more significant changes in INSIG2 and IRS2 genes. Furthermore, the effect of hypoxia on expression of these genes was mostly dependent on the ERN1 signaling enzyme function. The data also show that glucose or glutamine deprivation may change the expression of the genes studied and that the suppression of the ERN1 enzyme function usually modifies the effect of the glucose or glutamine deprivation. Results of this study demonstrated the dependence of INSR and related to insulin receptor signaling gene expressions in U87 glioma cells on ERN1 enzyme function indicating its participation in the regulation of metabolic and proliferative processes via endoplasmic reticulum stress which is important component of tumor growth and metabolic diseases. Moreover, hypoxia and glucose or glutamine deprivation are controlled by the expression of insulin receptor and related to insulin signaling genes mostly via ERN1 enzyme signaling.

Functional analysis of Dictyostelium IBARa reveals a conserved role of the I-BAR domain in endocytosis

I-BAR (inverse-Bin/amphiphysin/Rvs)-domain-containing proteins such as IRSp53 (insulin receptor substrate of 53 kDa) associate with outwardly curved membranes and connect them to proteins involved in actin dynamics. Research on I-BAR proteins has focussed on possible roles in filopod and lamellipod formation, but their full physiological function remains unclear. The social amoeba Dictyostelium encodes a single I-BAR/SH3 (where SH3 is Src homology 3) protein, called IBARa, along with homologues of proteins that interact with IRSp53 family proteins in mammalian cells, providing an excellent model to study its cellular function. Disruption of the gene encoding IBARa leads to a mild defect in development, but filopod and pseudopod dynamics are unaffected. Furthermore, ectopically expressed IBARa does not induce filopod formation and does not localize to filopods. Instead, IBARa associates with clathrin puncta immediately before they are endocytosed. This role is conserved: human BAIAP2L2 (brain-specific angiogenesis inhibitor 1-associated protein 2-like 2) also tightly co-localizes with clathrin plaques, although its homologues IRSp53 and IRTKS (insulin receptor tyrosine kinase substrate) associate with other punctate structures. The results from the present study suggest that I-BAR-containing proteins help generate the membrane curvature required for endocytosis and implies an unexpected role for IRSp53 family proteins in vesicle trafficking.

The mood stabilizer valproic acid activates the cytohesin-2-Arf6 signaling unit and induces abnormal neuritogenesis

IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor for Arf1 and Arf6, is localized at the postsynaptic density (PSD) and interacts with PSD-95. In this study, we identified a novel interaction of IQ-ArfGEF/BRAG1 with insulin receptor tyrosine kinase substrate of 53 kDa (IRSp53), also known as brain-specific angiogenesis inhibitor 1-associated protein 2. The interaction was mediated by the binding of the C-terminal proline-rich sequence of IQ-ArfGEF/BRAG1 to the SH3 domain of IRSp53. IQ-ArfGEF/BRAG1 and IRSp53 were colocalized at the PSD of excitatory synapses of certain neuronal populations. Our present findings suggest that IQ-ArfGEF/BRAG1 may play roles downstream of NMDA receptors through the interaction with multivalent PSD proteins such as IRSp53 and PSD-95.

The postsynaptic density protein, IQ-ArfGEF/BRAG1, can interact with IRSp53 through its proline-rich sequence

IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor for Arf1 and Arf6, is localized at the postsynaptic density (PSD) and interacts with PSD-95. In this study, we identified a novel interaction of IQ-ArfGEF/BRAG1 with insulin receptor tyrosine kinase substrate of 53 kDa (IRSp53), also known as brain-specific angiogenesis inhibitor 1-associated protein 2. The interaction was mediated by the binding of the C-terminal proline-rich sequence of IQ-ArfGEF/BRAG1 to the SH3 domain of IRSp53. IQ-ArfGEF/BRAG1 and IRSp53 were colocalized at the PSD of excitatory synapses of certain neuronal populations. Our present findings suggest that IQ-ArfGEF/BRAG1 may play roles downstream of NMDA receptors through the interaction with multivalent PSD proteins such as IRSp53 and PSD-95.

Comparative Phosphoproteomics of Zebrafish Fyn/Yes Morpholino Knockdown Embryos

The coordinated movement of cells is indispensable for normal vertebrate gastrulation. Several important players and signaling pathways have been identified in convergence and extension (CE) cell movements during gastrulation, including non-canonical Wnt signaling. Fyn and Yes, members of the Src family of kinases, are key regulators of CE movements as well. Here we investigated signaling pathways in early development by comparison of the phosphoproteome of wild type zebrafish embryos with Fyn/Yes knockdown embryos that display specific CE cell movement defects. For quantitation we used differential stable isotope labeling by reductive amination of peptides. Equal amounts of labeled peptides from wild type and Fyn/Yes knockdown embryos were mixed and analyzed by on-line reversed phase TiO(2)-reversed phase LC-MS/MS. Phosphorylated and non-phosphorylated peptides were quantified, and significant changes in protein expression and/or phosphorylation were detected. We identified 348 phosphoproteins of which 69 showed a decrease in phosphorylation in Fyn/Yes knockdown embryos and 72 showed an increase in phosphorylation. Among these phosphoproteins were known regulators of cell movements, including Adducin and PDLIM5. Our results indicate that quantitative phosphoproteomics combined with morpholino-mediated knockdowns can be used to identify novel signaling pathways that act in zebrafish development in vivo.

Serial Analysis of Gene Expression in Methamphetamine‐ and Phencyclidine‐Treated Rodent Cerebral Cortices: Are There Common Mechanisms?

Pharmacological actions of methamphetamine (METH) and phencyclidine (PCP) are different, but both of them can induce similar psychiatric disorders including abuse, intoxication, withdrawal, and psychotic symptoms like those of schizophrenia. These mental disorders are caused not only by their direct pharmacological effects, but also by secondary brain damage containing gene expression changes. In order to broadly grasp these alterations, we used serial analysis of gene expression (SAGE), a transcriptome analysis. We analyzed three cDNA libraries from cerebral cortices of saline (1 mL/kg)-, METH (4 mg/kg)-, or PCP (10 mg/kg)-treated Wistar rats (one hour after i.p. administration). The numbers of total tags were about 50,000 in each library, and approximately 18,000 kinds of tags were identified respectively. From the comparisons of three groups, we found both METH- and PCP-reactive genes. Upregulated genes contained calmodulin 2, stromal cell-derived factor receptor 1, brain-specific angiogenesis inhibitor 1-associated protein 2, ras homologue enriched in brain, basigin and thyrotropin-releasing hormone receptor. Downregulated genes contained lipocalin 2, aldolase A, importin 13, fatty acid binding protein 3, and glycine receptor alpha2 subunit. These data suggest important clues of common molecular basis in METH- and PCP-related psychiatric disorders.