TY - Generic T1 - RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms and GTPase binding in bipolar disorder. Y1 - 2014 A1 - Akula, N A1 - Barb, J A1 - Jiang, X A1 - Wendland, J R A1 - Choi, K H A1 - Sen, S K A1 - Hou, L A1 - Chen, D T W A1 - Laje, G A1 - Johnson, K A1 - Lipska, B K A1 - Kleinman, J E A1 - Corrada-Bravo, H A1 - Detera-Wadleigh, S A1 - Munson, P J A1 - McMahon, F J KW - Adult KW - Aged KW - Bipolar Disorder KW - Circadian Rhythm KW - Female KW - Genome-Wide Association Study KW - GTP Phosphohydrolases KW - HUMANS KW - Male KW - Meta-Analysis as Topic KW - Microarray Analysis KW - Middle Aged KW - Neuronal Plasticity KW - Polymerase Chain Reaction KW - Prefrontal Cortex KW - Principal Component Analysis KW - Sequence Analysis, RNA KW - Transcriptome KW - Young Adult AB -

RNA-sequencing (RNA-seq) is a powerful technique to investigate the complexity of gene expression in the human brain. We used RNA-seq to survey the brain transcriptome in high-quality postmortem dorsolateral prefrontal cortex from 11 individuals diagnosed with bipolar disorder (BD) and from 11 age- and gender-matched controls. Deep sequencing was performed, with over 350 million reads per specimen. At a false discovery rate of <5%, we detected five differentially expressed (DE) genes and 12 DE transcripts, most of which have not been previously implicated in BD. Among these, Prominin 1/CD133 and ATP-binding cassette-sub-family G-member2 (ABCG2) have important roles in neuroplasticity. We also show for the first time differential expression of long noncoding RNAs (lncRNAs) in BD. DE transcripts include those of serine/arginine-rich splicing factor 5 (SRSF5) and regulatory factor X4 (RFX4), which along with lncRNAs have a role in mammalian circadian rhythms. The DE genes were significantly enriched for several Gene Ontology categories. Of these, genes involved with GTPase binding were also enriched for BD-associated SNPs from previous genome-wide association studies, suggesting that differential expression of these genes is not simply a consequence of BD or its treatment. Many of these findings were replicated by microarray in an independent sample of 60 cases and controls. These results highlight common pathways for inherited and non-inherited influences on disease risk that may constitute good targets for novel therapies.

JA - Mol Psychiatry VL - 19 CP - 11 M3 - 10.1038/mp.2013.170 ER - TY - JOUR T1 - Distinct Rap1 activity states control the extent of epithelial invagination via α-catenin. JF - Dev Cell Y1 - 2013 A1 - Wang, Yu-Chiun A1 - Khan, Zia A1 - Wieschaus, Eric F KW - Actins KW - alpha Catenin KW - Animals KW - Cell Adhesion KW - Cell Adhesion Molecules KW - Cell Membrane KW - Cell Shape KW - Drosophila KW - Drosophila Proteins KW - Embryo, Nonmammalian KW - Enzyme Activation KW - Epithelial Cells KW - Genes, Insect KW - Green Fluorescent Proteins KW - GTP Phosphohydrolases KW - GTPase-Activating Proteins KW - Intercellular Junctions KW - RNA Interference KW - Time factors KW - Time-Lapse Imaging AB -

Localized cell shape change initiates epithelial folding, while neighboring cell invagination determines the final depth of an epithelial fold. The mechanism that controls the extent of invagination remains unknown. During Drosophila gastrulation, a higher number of cells undergo invagination to form the deep posterior dorsal fold, whereas far fewer cells become incorporated into the initially very similar anterior dorsal fold. We find that a decrease in α-catenin activity causes the anterior fold to invaginate as extensively as the posterior fold. In contrast, constitutive activation of the small GTPase Rap1 restricts invagination of both dorsal folds in an α-catenin-dependent manner. Rap1 activity appears spatially modulated by Rapgap1, whose expression levels are high in the cells that flank the posterior fold but low in the anterior fold. We propose a model whereby distinct activity states of Rap1 modulate α-catenin-dependent coupling between junctions and actin to control the extent of epithelial invagination.

VL - 25 CP - 3 M3 - 10.1016/j.devcel.2013.04.002 ER -