A critical role for protein tyrosine phosphatase nonreceptor type 5 in determining individual susceptibility to develop stress-related cognitive and morphological changes.
ABSTRACT While stressful life events confer increased risk for the development of psychopathology, most individuals experiencing adversity maintain normal psychological functioning, suggesting that individual differences may influence the susceptibility to develop stress-related psychiatric disorders. However, little is known about what determines this difference between individuals at the molecular level. In the present study, we identify that protein tyrosine phosphatase nonreceptor type 5 (PTPN5) (also known as STEP) is a critical determinant of differences in individual susceptibility to develop stress-related cognitive and morphological changes in rats. Our data demonstrate that ablation of PTPN5 expression delays physiological recovery from stress and augments the development of stress-related cognitive and morphological changes, whereas overexpression of a constitutively active variant of PTPN5 enhances the individual's resilience to stress. Our data also reveal that reduced PTPN5 expression prolongs the duration of extracellular signal-regulated kinase activation, leading to an elevation of Ca(V)1.2 channel expression and a recovery delay of K(V)4.2 channels from inactivation, which in turn heightens neuronal vulnerability to glutamate toxicity. Moreover, intraperitoneal injections of L-type Ca(2+) channel blocker nifedipine after stress resulted in a significantly lower rate for developing stress-related cognitive and morphological changes seen in PTPN5 knockdown rats. Together, these results identify a novel role for PTPN5 in mediating the development of stress-related cognitive and morphological changes and suggest that people with PTPN5 deficiency may have a greater susceptibility to capture the deleterious effects of stress.
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ABSTRACT: Uterus development during pre-implantation stage affects implantation process and embryo growth. Aberrant uterus development is associated with many human reproductive diseases. Among the factors regulating uterus development, vascular remodeling promoters are critical for uterus function and fertility. Vascular endothelial growth factor (VEGF), as one of the major members, has been found to be important in endothelial cell growth and blood vessel development, as well as in non-endothelial cells. VEGF mediation in reproduction has been broadly studied, but VEGF-induced transcriptional machinery during implantation window has not been systematically studied. In this study, a genetically repressed VEGF mouse model was used to analyze uterus transcriptome at gestation 2.5 (G2.5) by Solexa/Illumina's digital gene expression (DGE) system. A number of 831 uterus-specific and 2398 VEGF-regulated genes were identified. Gene ontology (GO) analysis indicated that genes actively involved in uterus development were members of collagen biosynthesis, cell proliferation and cell apoptosis. Uterus-specific genes were enriched in activities of phosphatidyl inositol phosphate kinase, histone H3-K36 demethylation and protein acetylation. Among VEGF-regulated genes, up-regulated were associated with RNA polymerase III activity while down-regulated were strongly related with muscle development. Comparable numbers of antisense transcripts were identified. Expression levels of the antisense transcripts were found tightly correlated with their sense expression levels, an indication of possibly non-specific transcripts generated around the active promoters and enhancers. The antisense transcripts with exceptionally high or low expression levels and the antisense transcripts under VEGF regulation were also identified. These transcripts may be important candidates in regulation of uterus development. This study provides a global survey on genes and antisense transcripts regulated by VEGF in the pre-implantation stage. Results will contribute to further study the candidate genes and pathways in regulating implantation process and related diseases.PLoS ONE 01/2013; 8(2):e57287. · 3.73 Impact Factor
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ABSTRACT: Probing molecular brain mechanisms related to increased suicide risk is an important issue in biological psychiatry research. Gene expression studies on post mortem brains indicate extensive changes prior to a successful suicide attempt; however, proteomic studies are scarce. Thus, we performed a DIGE proteomic analysis of post mortem tissue samples from the prefrontal cortex and amygdala of suicide victims to identify protein changes and biomarker candidates of suicide. Among our matched spots we found 46 and 16 significant differences in the prefrontal cortex and amygdala, respectively; by using the industry standard t test and 1.3 fold change as cut off for significance. Because of the risk of false discoveries (FDR) in these data, we also made FDR adjustment by calculating the q-values for all the t tests performed and by using 0.06 and 0.4 as alpha thresholds we reduced the number of significant spots to 27 and 9 respectively. From these we identified 59 proteins in the cortex and 11 proteins in the amygdala. These proteins are related to biological functions and structures such as metabolism, the redox system, the cytoskeleton, synaptic function, and proteolysis. Thirteen of these proteins (CBR1, DPYSL2, EFHD2, FKBP4, GFAP, GLUL, HSPA8, NEFL, NEFM, PGAM1, PRDX6, SELENBP1 and VIM,) have already been suggested to be biomarkers of psychiatric disorders at protein or genome level. We also pointed out 9 proteins that changed in both the amygdala and the cortex, and from these, GFAP, INA, NEFL, NEFM and TUBA1 are interacting cytoskeletal proteins that have a functional connection to glutamate, GABA, and serotonin receptors. Moreover, ACTB, CTSD and GFAP displayed opposite changes in the two examined brain structures that might be a suitable characteristic for brain imaging studies. The opposite changes of ACTB, CTSD and GFAP in the two brain structures were validated by western blot analysis.PLoS ONE 01/2012; 7(12):e50532. · 3.73 Impact Factor