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  • Proteomic and functional analyses reveal the role of chromatin reader SFMBT1 in regulating epigenetic silencing and the myogenic gene program. 23349461

    SFMBT1 belongs to the malignant brain tumor domain-containing chromatin reader family that recognizes repressive histone marks and represses transcription. The biological functions and molecular basis underlying SFMBT1-mediated transcriptional repression are poorly elucidated. Here, our proteomic analysis revealed that SFMBT1 is associated with multiple transcriptional corepressor complexes, including CtBP/LSD1/HDAC complexes, polycomb repressive complexes, and malignant brain tumor family proteins, that collectively contribute to SFMBT1 repressor activity. During myogenesis, Sfmbt1 represses myogenic differentiation of cultured and primary myoblasts. Mechanistically, Sfmbt1 interacts with MyoD and mediates epigenetic silencing of MyoD target genes via recruitment of its associated corepressors and subsequent induction of epigenetic modifications and chromatin compaction. Therefore, our study identified novel mechanisms accounting for SFMBT1-mediated transcription repression and revealed an essential role of Sfmbt1 in regulating MyoD-mediated transcriptional silencing that is required for the maintenance of undifferentiated states of myogenic progenitor cells.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • Novel roles for metallothionein-I + II (MT-I + II) in defense responses, neurogenesis, and tissue restoration after traumatic brain injury: insights from global gene expr ... 16941634

    Traumatic injury to the brain is one of the leading causes of injury-related death or disability, especially among young people. Inflammatory processes and oxidative stress likely underlie much of the damage elicited by injury, but the full repertoire of responses involved is not well known. A genomic approach, such as the use of microarrays, provides much insight in this regard, especially if combined with the use of gene-targeted animals. We report here the results of one of these studies comparing wild-type and metallothionein-I + II knockout mice subjected to a cryolesion of the somatosensorial cortex and killed at 0, 1, 4, 8, and 16 days postlesion (dpl) using Affymetrix genechips/oligonucleotide arrays interrogating approximately 10,000 different murine genes (MG_U74Av2). Hierarchical clustering analysis of these genes readily shows an orderly pattern of gene responses at specific times consistent with the processes involved in the initial tissue injury and later regeneration of the parenchyma, as well as a prominent effect of MT-I + II deficiency. The results thoroughly confirmed the importance of the antioxidant proteins MT-I + II in the response of the brain to injury and opened new avenues that were confirmed by immunohistochemistry. Data in KO, MT-I-overexpressing, and MT-II-injected mice strongly suggest a role of these proteins in postlesional activation of neural stem cells.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AB3066
    Nombre del producto:
    Anti-Aquaporin 2 Antibody

  • Knockdown of long non-coding RNA XIST exerts tumor-suppressive functions in human glioblastoma stem cells by up-regulating miR-152. 25578780

    Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Great interest persists in useful therapeutic targets in GBM. Aberrant expression of long non-coding RNAs (lncRNAs) has been functionally associated with many cancers. Here, we elucidated the function and the possible molecular mechanisms of lncRNA XIST in human glioblastoma stem cells (GSCs). Our results proved that XIST expression was up-regulated in glioma tissues and GSCs. Functionally, knockdown of XIST exerted tumor-suppressive functions by reducing cell proliferation, migration and invasion as well as inducing apoptosis. The in vivo studies also showed that knockdown of XIST suppressed tumor growth and produced high survival in nude mice. Further, there was reciprocal repression between XIST and miR-152. Mechanistic investigations defined the direct binding ability of the predicted miR-152 binding site on the XIST. In addition, XIST and miR-152 are probably in the same RNA induced silencing complex (RISC). Finally, miR-152 mediated the tumor-suppressive effects that knockdown of XIST exerted. Taken together, these results provided a comprehensive analysis of XIST in GSCs and important clues for understanding the key roles of lncRNA-miRNA functional network in human glioma.
    Tipo de documento:
    Referencia
    Referencia del producto:
    17-701
    Nombre del producto:
    EZ-Magna RIP™ RNA-Binding Protein Immunoprecipitation Kit

  • The angiogenic factor angiopoietin-1 is a proneurogenic peptide on subventricular zone stem/progenitor cells. 20357108

    In the adult mammalian brain, the subventricular zone (SVZ) hosts stem cells constantly generating new neurons. Angiopoietin-1 (Ang-1) is an endothelial growth factor with a critical role in division, survival, and adhesion of endothelial cells via Tie-2 receptor activity. Expression of Tie-2 in nonendothelial cells, especially neurons and stem cells, suggests that Ang-1 may be involved in neurogenesis. In the present work, we investigated the putative role of Ang-1 on SVZ neurogenesis. Immature cells from SVZ-derived neurospheres express Ang-1 and Tie-2 mRNA, suggesting a role for the Ang-1/Tie-2 system in the neurogenic niche. Moreover, we also found that Tie-2 protein expression is retained on differentiation in neurons and glial cells. Ang-1 triggered proliferation via activation of the ERK1/2 (extracellular signal-regulated kinase 1/2) mitogen-activated protein kinase (MAPK) kinase pathway but did not induce cell death. Accordingly, coincubation with an anti-Tie-2 neutralizing antibody prevented the pro-proliferative effect of Ang-1. Furthermore, Ang-1 increased the number of NeuN (neuronal nuclear protein)-positive neurons in cultures treated for 7 d, as well as the number of functional neurons, as assessed by monitoring [Ca(2+)](i) rises after application of specific stimuli for neurons and immature cells. The proneurogenic effect of Ang-1 is mediated by Tie-2 activation and subsequent mTOR (mammalian target of rapamycin kinase) mobilization. In agreement, neuronal differentiation significantly decreased after exposure to an anti-Tie-2 neutralizing antibody and to rapamycin. Moreover, Ang-1 elicited the activation of the SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase) MAPK, involved in axonogenesis. Our work shows a proneurogenic effect of Ang-1, highlighting the relevance of blood vessel/stem cell cross talk in health and disease.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • All JNKs can kill, but nuclear localization is critical for neuronal death. 18474608

    JNKs are implicated in a range of brain pathologies and receive considerable attention as potential therapeutic targets. However, JNKs also regulate physiological and homeostatic processes. An attractive hypothesis from the drug development perspective is that distinct JNK isoforms mediate "physiological" and "pathological" responses. However, this lacks experimental evaluation. Here we investigate the isoforms, subcellular pools, and c-Jun/ATF2 targets of JNK in death of central nervous system neurons following withdrawal of trophic support. We use gene knockouts, gene silencing, subcellularly targeted dominant negative constructs, and pharmacological inhibitors. Combined small interfering RNA knockdown of all JNKs 1, 2, and 3, provides substantial neuroprotection. In contrast, knockdown or knock-out of individual JNKs or two JNKs together does not protect. This explains why the evidence for JNK in neuronal death has to date been largely pharmacological. Complete knockdown of c-Jun and ATF2 using small interfering RNA also fails to protect, casting doubt on c-Jun as a critical effector of JNK in neuronal death. Nonetheless, the death requires nuclear but not cytosolic JNK activity as nuclear dominant negative inhibitors of JNK protect, whereas cytosolic inhibitors only block physiological JNK function. Thus any one of the three JNKs is capable of mediating apoptosis and inhibition of nuclear JNK is protective.
    Tipo de documento:
    Referencia
    Referencia del producto:
    06-748

  • Increased microglia/macrophage gene expression in a subset of adult and pediatric astrocytomas. 22937035

    Glioblastoma (GBM) is a highly malignant brain tumor with a dismal prognosis. Gene expression profiling of GBM has revealed clinically relevant tumor subtypes, and this provides exciting opportunities to better understand disease pathogenesis. Results from an increasing number of studies demonstrate a role for the immune response in cancer progression, yet it is unclear how the immune response differs across tumor subtypes and how it affects outcome. Utilizing gene expression data from The Cancer Genome Atlas Project and the Gene Expression Omnibus database, we demonstrate an enrichment of immune response-related gene expression in the mesenchymal subtype of adult GBM (n = 173) and pediatric high-grade gliomas (n = 53). In an independent cohort of pediatric astrocytomas (n = 24) from UCSF, we stratified tumors into subtypes and confirmed these findings. Using novel immune cell-specific gene signatures we demonstrate selective enrichment of microglia/macrophage-related genes in adult and pediatric GBM tumors of the mesenchymal subtype. Furthermore, immunostaining of adult GBM tumors showed significantly higher cell numbers of microglia/macrophages in mesenchymal versus non-mesenchymal tumors (p = 0.04). Interestingly, adult GBM tumors with the shortest survival had significant enrichment of microglia/macrophage-related genes but this was not true for pediatric GBMs. Consistent with an association with poor outcome, immune response-related genes were highly represented in an adult poor prognosis gene signature, with the expression of genes related to macrophage recruitment and activation being most strongly associated with survival (pless than 0.05) using CoxBoost multivariate modeling. Using a microglia/macrophage high gene signature derived from quantification of tumor-infiltrating cells in adult GBM, we identified enrichment of genes characteristic of CD4 T cells, granulocytes, and microglia/macrophages (n = 573). These studies support a role for the immune response, particularly the microglia/macrophage response, in the biology of an important subset of GBM. Identification of this subset may be important for future therapeutic stratification.
    Tipo de documento:
    Referencia
    Referencia del producto:
    CBL496
    Nombre del producto:
    Anti-CD34 Class II Antibody, clone QBEND/10

  • Mechanisms involved in development of retinotectal connections: roles of Eph receptor tyrosine kinases, NMDA receptors and nitric oxide. 9932438

    Axons of retinal ganglion cells exhibit a specific pattern of connections with the brain. Within each visual nucleus in the brain, retinal connections are topographic such that axons from neighboring ganglion cells have neighboring synapses. Research is beginning to shed light on the mechanisms responsible for development of topographic connections in the visual system. Much of this research is focused on the axonal connections of the retina with the tectum. In vivo and in vitro experiments indicate that the pattern of retinotectal connections develops in part due to positional labels carried by the growing retinal axons and by the tectal cells. Evidence suggests that gradients of Eph receptor tyrosine kinases serve as positional labels on the growing retinal axons, and gradients of ligands for these receptors serve as positional labels in the tectum. Blocking expression of EphA3, a receptor tyrosine kinase, in the developing retina resulted in disruption of the topography of the retinotectal connections, further supporting the role of these, molecules. Although positional labels appear to be important, other mechanisms must also be involved. The initial pattern of retinotectal connections lacks the precision seen in the adult. The adult pattern of connections arises during development by activity dependent refinement of a roughly ordered prepattern. The refinement process results in elimination of projections to the wrong side of the brain, to non-visual nuclei and to inappropriate regions within a nucleus. Blocking NMDA receptors during the period of refinement preserved anomalous retinotectal projections, which suggests that elimination of these projections is mediated by NMDA receptors. Furthermore, tectal cells normally express high levels of nitric oxide synthase (NOS) during the period of refinement, and blocking nitric oxide (NO) synthesis also preserved inappropriate projections. Thus, both NMDA receptors and NO appear to be involved in refinement. Blocking NMDA receptor activation reduced NOS activity in tectal cells, which suggests the possibility that NO is the downstream mediator of NMDA function related to refinement. A quantitative comparison of blocking NMDA receptors, NO synthesis or both showed that all three treatments have comparable effects on refinement. This indicates that the role of NMDA receptor activation relative to refinement may be completely mediated through nitric oxide. Quantitative analysis also suggests that other mechanisms not involving NMDA receptors or NO must be involved in refinement. Other mechanisms appear to include cell death.
    Tipo de documento:
    Referencia
    Referencia del producto:
    14-644
    Nombre del producto:
    EphA3 Protein, active, 10 µg

  • Activity requires soluble amyloid precursor protein alpha to promote neurite outgrowth in neural stem cell-derived neurons via activation of the MAPK pathway. 18717733

    It is known that activity modulates neuronal differentiation in the adult brain but the signalling mechanisms underlying this process remain to be identified. We show here that activity requires soluble amyloid precursor protein (sAPP) to enhance neurite outgrowth of young neurons differentiating from neural stem cells. Inhibition of sAPP secretion and anti-APP antibodies both abolished the effect of depolarization on neurite outgrowth, whereas exogenous sAPPalpha, similar to depolarization, induced neurite elongation. Depolarization and sAPPalpha both required active N-methyl-D-aspartic acid receptor (NMDAR) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) recruitment to induce neurite outgrowth. However, depolarization and sAPPalpha played different roles in modulating this signalling cascade. Depolarization induced ERK phosphorylation with fast kinetics via activation of NMDAR. By contrast, acute application of sAPPalpha did not lead to ERK activation. However, continuous generation of sAPPalpha was necessary for depolarization-induced ERK phosphorylation, indicating that sAPPalpha promotes MAPK/ERK recruitment by an indirect mechanism. In addition, we found that blockade of NMDAR down-regulated APP expression, whereas depolarization increased sAPPalpha, suggesting that activity may also act upstream of sAPP signalling by regulating the amount of cellular APP and extracellular sAPPalpha. Finally, we show that soluble amyloid precursor-like protein 2 (sAPLP2), but not sAPLP1, is functionally redundant to sAPP in promoting neurite outgrowth and that soluble members of the APP family require membrane-bound APP to enhance neurite outgrowth. In summary, these experiments indicate a novel role of APP family members in activity-dependent neuronal differentiation.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB348
    Nombre del producto:
    Anti-APP A4 Antibody, a.a. 66-81 of APP {NT}, clone 22C11

  • Metabotropic glutamate receptor 4-immunopositive terminals of medium-sized spiny neurons selectively form synapses with cholinergic interneurons in the rat neostriatum. 17177262

    Metabotropic glutamate receptor 4 (mGluR4) is localized mainly to presynaptic membranes in the brain. Rat neostriatum has been reported to contain two types of mGluR4-immunoreactive axon varicosities: small, weakly immunoreactive varicosities that were distributed randomly (type 1) and large, intensely immunoreactive ones that were often aligned linearly (type 2). In the present study, most type 1 terminals formed asymmetric synapses on dendritic spines, whereas type 2 terminals made symmetric synapses on dendritic shafts, showing immunoreactivity for GABAergic markers. After depletion of neostriatal neurons, type 2 but not type 1 varicosities were largely decreased in the damaged region. When medium-sized spiny neurons (MSNs) were labeled with Sindbis virus expressing membrane-targeted green fluorescent protein, mGluR4 immunoreactivity was observed on some varicosities of their axon collaterals in immunofluorescence and immunoelectron microscopies. Furthermore, type 2 varicosities were often positive for substance P but mostly negative for striatal interneuron markers and preproenkephalin. Thus, striatonigral/striato-entopeduncular MSNs are likely to be the largest source of type 2 mGluR4-immunopositive axon terminals in the neostriatum. Next, in the double-immunofluorescence study, almost all choline acetyltransferase (ChAT)-immunopositive and 41% of NK1 receptor-positive dendrites were heavily associated with type 2 mGluR4-immunoreactive varicosities. Neuronal nitric oxide synthase (nNOS)-positive dendrites, in contrast, seemed associated with only a few type 2 varicosities. Conversely, almost all type 2 varicosities were closely apposed to NK1 receptor-positive dendrites that were known to be derived from cholinergic and nNOS-producing interneurons. These findings indicate that the mGluR4-positive terminals of MSN axon collaterals selectively form synapses with neostriatal cholinergic interneurons.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AP184B
    Nombre del producto:
    Donkey Anti-Sheep IgG Antibody, biotin-SP conjugate, Species Adsorbed

  • Age-dependent decrease in glutamine synthetase expression in the hippocampal astroglia of the triple transgenic Alzheimer's disease mouse model: mechanism for deficient g ... 21801442

    Astrocytes are fundamental for brain homeostasis and the progression and outcome of many neuropathologies including Alzheimer's disease (AD). In the triple transgenic mouse model of AD (3xTg-AD) generalised hippocampal astroglia atrophy precedes a restricted and specific β-amyloid (Aβ) plaque-related astrogliosis. Astrocytes are critical for CNS glutamatergic transmission being the principal elements of glutamate homeostasis through maintaining its synthesis, uptake and turnover via glutamate-glutamine shuttle. Glutamine synthetase (GS), which is specifically expressed in astrocytes, forms glutamine by an ATP-dependent amination of glutamate. Here, we report changes in GS astrocytic expression in two major cognitive areas of the hippocampus (the dentate gyrus, DG and the CA1) in 3xTg-AD animals aged between 9 and 18 months. We found a significant reduction in Nv (number of cell/mm3) of GS immunoreactive (GS-IR) astrocytes starting from 12 months (28.59%) of age in the DG, and sustained at 18 months (31.65%). CA1 decrease of GS-positive astrocytes Nv (33.26%) occurs at 18 months. This Nv reduction of GS-IR astrocytes is paralleled by a decrease in overall GS expression (determined by its optical density) that becomes significant at 18 months (21.61% and 19.68% in DG and CA1, respectively). GS-IR Nv changes are directly associated with the presence of Aβ deposits showing a decrease of 47.92% as opposed to 23.47% in areas free of Aβ. These changes in GS containing astrocytes and GS-immunoreactivity indicate AD-related impairments of glutamate homeostatic system, at the advanced and late stages of the disease, which may affect the efficacy of glutamatergic transmission in the diseased brain that may contribute to the cognitive deficiency.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB302
    Nombre del producto:
    Anti-Glutamine Synthetase Antibody, clone GS-6