Neuro-inflammation and neuronal communication are considered as mis-regulated processes in the aetiology and pathology of bipolar disorder (BD). Which and when specific signal pathways become abnormal during the ontogeny of bipolar disorder patients is unknown. To address this question, we applied induced pluripotent stem cell (iPSC) technology followed by cortical neural differentiation on adipocyte-derived cells from BD type I patients (with psychotic episodes in psychiatric history) and healthy volunteers (controls). RNA sequencing in iPSC and cortical neural stem cell (NSC) lines were used to examine alterations between the transcriptomes from BD I and control samples during transition from the pluripotent stage towards the neural developmental stage. At the iPSC stage, the most highly significant differentially expressed gene (DEG) was the NLRP2 inflammasome (P=2.66 × 10−10). Also among 42 DEGs at the NSC stage, NLRP2 showed the strongest statistical significance (P=3.07 × 10−19). In addition, we have also identified several cytoskeleton-associated genes as DEGs from the NSC stage, such as TMP2, TAGLN and ACTA2; the former two genes are recognised for the first time to be associated with BD. Our results also suggest that iPSC-derived BD-cortical NSCs carry several abnormalities in dopamine and GABA receptor canonical pathways, underlining that our in vitro BD model reflects pathology in the central nervous system. This would indicate that mis-regulated gene expression of inflammatory, neurotransmitter and cytoskeletal signalling occurs during early fetal brain development of BD I patients.

Identification of causative genetic variants leading to the development of bipolar disorder (BD) could result in genetic tests that would facilitate diagnosis. A better understanding of affected genes and pathways is also necessary for targeting of genes that may improve treatment strategies. To date several susceptibility genes have been reported from genome-wide association studies (GWAS), but little is known about specific variants that affect disease development. Here, we performed quantitative proteomics and whole-genome sequencing (WGS). Quantitative proteomics revealed NLRP2 as the most significantly up-regulated protein in neural stem cells and mature neural cells obtained from BD-patient cell samples. These results are in concordance with our previously published transcriptome analysis. Furthermore, the levels of FEZ2 and CADM2 proteins were also significantly differentially expressed in BD compared to control derived cells. The levels of FEZ2 were significantly downregulated in neural stem cells (NSC) while CADM2 was significantly up-regulated in mature neuronal cell culture. Promising novel candidate mutations were identified in the ANK3, NEK3, NEK7, TUBB, ANKRD1, and BRD2 genes. A literature search of candidate variants and deregulated proteins revealed that there are several connections to microtubule function for the molecules putatively involved. Microtubule function in neurons is critical for axon structure and axonal transport. A functional dynamic microtubule is also needed for an advocate response to cellular and environmental stress. If microtubule dynamics is compromised by mutations, it could be followed by deregulated expression forming a possible explanation for the inherited vulnerability to stressful life events that have been proposed to trigger mood episodes in BD patients.

Background The human orphan receptor TLX (NR2E1) is a key regulator of neurogenesis, adult stem cell maintenance, and tumorigenesis. However, little is known about the genetic and transcriptomic events that occur following TLX overexpression in human cell lines. Aims Here, we used cytogenetics and RNA sequencing to investigate the effect of TLX overexpression with an inducible vector system in the HEK 293T cell line. Methods and results Conventional spectral karyotyping was used to identify chromosomal abnormalities, followed by fluorescence in situ hybridization (FISH) analysis on chromosome spreads to assess TLX DNA copy number. Illumina paired‐end whole transcriptome sequencing was then performed to characterize recurrent genetic variants (single nucleotide polymorphisms (SNPs) and indels), expressed gene fusions, and gene expression profiles. Lastly, flow cytometry was used to analyze cell cycle distribution. Intriguingly, we show that upon transfection with a vector containing the human TLX gene (eGFP‐hTLX), an isochromosome forms on the long arm of chromosome 6, thereby resulting in DNA gain of the TLX locus (6q21) and upregulation of TLX. Induction of the eGFP‐hTLX vector further increased TLX expression levels, leading to G0‐G1 cell cycle arrest, genetic aberrations, modulation of gene expression patterns, and crosstalk with other nuclear receptors (AR, ESR1, ESR2, NR1H4, and NR3C2). We identified a 49‐gene signature associated with central nervous system (CNS) development and carcinogenesis, in addition to potentially cancer‐driving gene fusions (LARP1‐CNOT8 and NSL1‐ZDBF2) and deleterious genetic variants (frameshift insertions in the CTSH, DBF4, POSTN, and WDR78 genes). Conclusion Taken together, these findings illustrate that TLX may play a pivotal role in tumorigenesis via genomic instability and perturbation of cancer‐related processes.