Abnormal gene expression of BDNF, but not BDNF-AS, in iPSC, neural stem cells and postmortem brain samples from bipolar disorder.

Background: Brain-derived neurotrophic factor (BDNF) antisense RNA (BDNF-AS) was identified as naturally conserved non-coding antisense RNA that suppresses the transcription of BDNF.

Methods: We measured the expression of BDNF mRNA and BDNF-AS mRNA in iPSC and NSC from bipolar disorder (BD) patients and healthy control subjects, and postmortem brain samples such as the corpus callosum, the Brodmann area (BA8), and BA46 from BD patients and age- and sex-matched controls.

Results: The expression of BDNF mRNA in iPSC from BD patients (n = 6) was significantly lower than that of control subjects (n = 4) although the expression of BDNF mRNA in NSC from BD patients was significantly higher than that of control subjects.

Differential acute impact of therapeutically effective and overdose concentrations of lithium on human neuronal single cell and network function.

Lithium salts are used as mood-balancing medication prescribed to patients suffering from neuropsychiatric disorders, such as bipolar disorder and major depressive disorder. Lithium salts cross the blood-brain barrier and reach the brain parenchyma within few hours after oral application, however, how lithium influences directly human neuronal function is unknown. We applied patch-clamp and microelectrode array technology on human induced pluripotent stem cell (iPSC)-derived cortical neurons acutely exposed to therapeutic (<1 mM) and overdose concentrations (>1 mM) of lithium chloride (LiCl) to assess how therapeutically effective and overdose concentrations of LiCl directly influence human neuronal electrophysiological function at the synapse, single-cell, and neuronal network level.

TGF-β1 Suppresses Proliferation and Induces Differentiation in Human iPSC Neural Models.

Persistent neural stem cell (NSC) proliferation is, among others, a hallmark of immaturity in human induced pluripotent stem cell (hiPSC)-based neural models. TGF-β1 is known to regulate NSCs during embryonic development in rodents. Here we examined the role of TGF-β1 as a potential candidate to promote differentiation of hiPSCs-derived NSCs and maturation of neuronal progenies.

Identification of candidate genetic variants and altered protein expression in neural stem and mature neural cells support altered microtubule function to be an essential component in bipolar disorder.

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.

Tumorigenic effects of TLX overexpression in HEK 293T cells.

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.

Robust Generation of Person-Specific, Synchronously Active Neuronal Networks Using Purely Isogenic Human iPSC-3D Neural Aggregate Cultures.

Reproducibly generating human induced pluripotent stem cell-based functional neuronal circuits, solely obtained from single individuals, poses particular challenges to achieve personalized and patient specific functional neuronal models. A hallmark of functional neuronal assemblies, synchronous neuronal activity, can be non-invasively studied by microelectrode array (MEA) technology, reliably capturing physiological and pathophysiological aspects of human brain function. In our here presented manuscript, we demonstrate a procedure to generate 3D neural aggregates comprising astrocytes, oligodendroglial cells, and neurons obtained from the same human tissue sample.

Telomere Function and the G-Quadruplex Formation are Regulated by hnRNP U.

We examine the role of the heterogenous ribonucleoprotein U (hnRNP U) as a G-quadruplex binding protein in human cell lines. Hypothesizing that hnRNP U is associated with telomeres, we investigate what other telomere-related functions it may have. Telomeric G-quadruplexes have been fully characterized in vitro, but until now no clear evidence of their function or in vivo interactions with proteins has been revealed in mammalian cells.

Comparison of the glycosphingolipids of human-induced pluripotent stem cells and human embryonic stem cells.

High expectations are held for human-induced pluripotent stem cells (hiPSC) since they are established from autologous tissues thus overcoming the risk of allogeneic immune rejection when used in regenerative medicine. However, little is known regarding the cell-surface carbohydrate antigen profile of hiPSC compared with human embryonic stem cells (hESC). Here, glycosphingolipids were isolated from an adipocyte-derived hiPSC line, and hiPSC and hESC glycosphingolipids were compared by concurrent characterization by binding assays with carbohydrate-recognizing ligands and mass spectrometry.

ASK1 regulates the survival of neuroblastoma cells by interacting with TLX and stabilizing HIF-1α.

Elevated expression of TLX (also called as NR2E1) in neuroblastoma (NB) correlates with unfavorable prognosis, and TLX is required for self-renewal of NB cells. Knockdown of TLX has been shown to reduce the NB sphere-forming ability. ASK1 (MAP3K5) and TLX expression are both enhanced in SP (side population) NB and patient-derived primary NB sphere cell lines, but the majority of non-SP NB lines express lower ASK1 expression.

Nuclear receptor TLX inhibits TGF-β signaling in glioblastoma.

TLX (also called NR2E1) is an orphan nuclear receptor that maintains stemness of neuronal stem cells. TLX is highly expressed in the most malignant form of glioma, glioblastoma multiforme (GBM), and is important for the proliferation and maintenance of the stem/progenitor cells of the tumor. Transforming Growth Factor-β (TGF-β) is a cytokine regulating many different cellular processes such as differentiation, migration, adhesion, cell death and proliferation.

TLX-Its Emerging Role for Neurogenesis in Health and Disease.

The orphan nuclear receptor TLX, also called NR2E1, is a factor important in the regulation of neural stem cell (NSC) self-renewal, neurogenesis, and maintenance. As a transcription factor, TLX is vital for the expression of genes implicated in neurogenesis, such as DNA replication, cell cycle, adhesion and migration. It acts by way of repressing or activating target genes, as well as controlling protein-protein interactions.

Proteomics of dedifferentiation of SK-N-BE2 neuroblastoma cells.

Neuroblastoma develops through processes which include cellular dedifferentiation. Ability of tumors to form spheroids is one of the manifestations of dedifferentiation and carcinogenic transformation. To study mechanisms of dedifferentiation of neuroblastoma cells, we generated spheroids and performed a proteomics study to compare the spheroids with parental SK-N-BE2 cells.

Abnormality in serum levels of mature brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in mood-stabilized patients with bipolar disorder: a study of two independent cohorts.

Background: Early detection and diagnosis of bipolar disorder can be difficult. Tools are needed to help clinicians detect bipolar disorder earlier, which would ameliorate the prognosis.

Methods: ELISA kits that distinguish between mature brain derived neurotrophic factor (BDNF) and proBDNF, we compared serum levels of mature BDNF, proBDNF, and matrix metalloproteinase-9 (MMP-9) in two independent cohorts (Sahlgrenska cohort and Karolinska cohort) of mood-stabilized bipolar patients and healthy controls.

The roles of PDGF in development and during neurogenesis in the normal and diseased nervous system.

The four platelet-derived growth factor (PDGF) ligands and PDGF receptors (PDGFRs), α and β (PDGFRA, PDGFRB), are essential proteins that are expressed during embryonic and mature nervous systems, i.e., in neural progenitors, neurons, astrocytes, oligodendrocytes, and vascular cells.

TLX controls angiogenesis through interaction with the von Hippel-Lindau protein.

TLX is known as the orphan nuclear receptor indispensable for maintaining neural stem cells in adult neurogenesis. We report here that neuroblastoma cell lines express high levels of TLX, which further increase in hypoxia to enhance the angiogenic capacity of these cells. The proangiogenetic activity of TLX appears to be induced by its direct binding to the von Hippel-Lindau protein (pVHL), which stabilizes TLX.

Cis-regulation of microRNA expression by scaffold/matrix-attachment regions.

microRNAs (miRNAs) spatio-temporally modulate gene expression; however, very little is known about the regulation of their expression. Here, we hypothesized that the well-known cis-regulatory elements of gene expression, scaffold/matrix-attachment regions (MARs) could modulate miRNA expression. Accordingly, we found MARs to be enriched in the upstream regions of miRNA genes.

Network modeling of the transcriptional effects of copy number aberrations in glioblastoma.

DNA copy number aberrations (CNAs) are a hallmark of cancer genomes. However, little is known about how such changes affect global gene expression. We develop a modeling framework, EPoC (Endogenous Perturbation analysis of Cancer), to (1) detect disease-driving CNAs and their effect on target mRNA expression, and to (2) stratify cancer patients into long- and short-term survivors.

Nuclear orphan receptor TLX induces Oct-3/4 for the survival and maintenance of adult hippocampal progenitors upon hypoxia.

Hypoxia promotes neural stem cell proliferation, the mechanism of which is poorly understood. Here, we have identified the nuclear orphan receptor TLX as a mediator for proliferation and pluripotency of neural progenitors upon hypoxia. We found an enhanced early protein expression of TLX under hypoxia potentiating sustained proliferation of neural progenitors.

Exogenous introduction of tissue inhibitor of metalloproteinase 2 reduces accelerated growth of TGF-β-disrupted diffuse-type gastric carcinoma.

Diffuse-type gastric carcinoma is characterized by rapid progression and poor prognosis. High expression of transforming growth factor (TGF)-β and thick stromal fibrosis are observed in this type of gastric carcinoma. We have previously shown that disruption of TGF-β signaling via introduction of a dominant negative form of the TGF-β type II receptor (dnTβRII) into diffuse-type gastric cancer cell lines, including OCUM-2MLN, caused accelerated tumor growth through induction of tumor angiogenesis in vivo.

TLX activates MASH1 for induction of neuronal lineage commitment of adult hippocampal neuroprogenitors.

The orphan nuclear receptor TLX has been proposed to act as a repressor of cell cycle inhibitors to maintain the neural stem cells in an undifferentiated state, and prevents commitment into astrocyte lineages. However, little is known about the mechanism of TLX in neuronal lineage commitment and differentiation. A majority of adult rat hippocampus-derived progenitors (AHPs) cultured in the presence of FGF express a high level of TLX and a fraction of these cells also express the proneural gene MASH1.

Platelet-derived growth factor-mediated induction of the synaptic plasticity gene Arc/Arg3.1.

Platelet-derived growth factor (PDGF) is a pleiotropic protein with critical roles in both developmental as well as pathogenic processes. In the central nervous system specifically, PDGF is critical for neuronal proliferation and differentiation and has also been implicated as a neuroprotective agent. Whether PDGF also plays a role in synaptic plasticity, however, remains poorly understood.

Molecular mechanisms involving sigma receptor-mediated induction of MCP-1: implication for increased monocyte transmigration.

Cocaine abuse hastens the neurodegeneration often associated with advanced HIV-1 infection. The mechanisms, in part, revolve around the neuroinflammatory processes mediated by the chemokine monocyte chemotactic protein-1 (MCP-1/CCL2). Understanding factors that modulate MCP-1 and, in turn, facilitate monocyte extravasation in the brain is thus of paramount importance.

Dysregulation of platelet-derived growth factor beta-receptor expression by DeltaNp73 in neuroblastoma.

We have previously characterized how p53 family proteins control the transcriptional regulation of the platelet-derived growth factor beta-receptor (PDGFRB) and found that DeltaNp73alpha, acting dominant-negatively to p53 and p73, can upregulate PDGFRB promoter activity. Here, we report that PDGFRB regulation differs between two neuroblastoma cell lines, correlating with the actions of DeltaNp73. We found that PDGFRB was highly expressed in IMR-32 cells, and serum stimulation of IMR-32 cells did not downregulate PDGFRB expression, as seen in SH-SY5Y cells.

Hypercholesterolemia leads to elevated TGF-beta1 activity and T helper 3-dependent autoimmune responses in atherosclerotic mice.

Objective: The pathogenesis of atherosclerosis involves inflammation and immune reactions. Low-density lipoproteins accumulate and are oxidized (oxLDL) in the arterial intima during hypercholesterolemia, leading to activation of endothelial cells, macrophages and T cells. We have previously found that severe hypercholesterolemia can induce a switch of autoimmune responses from T helper (Th)1 to Th2 effector type in atherosclerotic apoE knockout (E0) mice.

Kinetics of repression by modified p53 on the PDGF beta-receptor promoter.

Herein, we show that both exogenously transfected and endogenously activated p53 repress promoter activity and expression of PDGFRB. p53 binds the proximal promoter containing the CCAAT motif as examined by EMSA and chromatin immunoprecipitation. However, gradual induction of p53 in tet-onSAOS2 cells resulted in a transient increase of the PDGFRB-promoter activity and its expression.