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  • Co-expression of cyclin D1 and phosphorylated ribosomal S6 proteins in hemimegalencephaly. 17483958

    Hemimegalencephaly (HMEG) is a developmental brain malformation highly associated with epilepsy. Balloon cells (BCs) and cytomegalic neurons (CNs) are frequently observed in HMEG specimens. Cytomegaly in developmental brain malformations may reflect in aberrant activation of the mTOR and beta-catenin signaling cascades, known regulators of cell size. We hypothesized that there is aberrant co-expression of phospho-ribosomal S6 (P-S6) protein, a downstream effector of the mTOR cascade, as well as cyclin D1, a downstream effector of the beta-catenin pathway, in BCs and cytomegalic neurons in HMEG. We hypothesized that mutations in PTEN (a cause of HMEG associated with Proteus syndrome), TSC1 or TSC2 (tuberous sclerosis complex) genes, which are known to modulate beta-catenin and mTOR signaling could cause sporadic HMEG. Expression of cyclin D1, phospho-p70 S6 kinase (P-p70S6K, another mTOR cascade kinase), P-S6, MAP2, NeuN, or GFAP was determined by immunohistochemistry in HMEG brain tissue (n = 7 specimens). Cyclin D1, P-p70S6K, and P-S6 proteins were co-localized in BCs and CNs in the enlarged hemisphere but not in the unaffected hemisphere or in morphologically normal tissue. Cyclin D1 and P-S6 proteins were not detected in GFAP-labeled astrocytes. Sequencing of PTEN, TSC1, and TSC2 genes in cytomegalic cells co-expressing cyclin D1 and P-S6 proteins did not reveal mutations. Selective expression of cyclin D1 and P-S6 in cytomegalic cells in HMEG suggests co-activation of the beta-catenin and mTOR cascades. PTEN, TSC1, or TSC2 gene mutations were not detected suggesting that sporadic HMEG is distinct from HMEG associated with Proteus syndrome or tuberous sclerosis complex.
    Document Type:
    Reference
    Product Catalog Number:
    MAB377
    Product Catalog Name:
    Anti-NeuN Antibody, clone A60

  • Involvement of the Notch pathway in terminal astrocytic differentiation: role of PKA. 24286475

    The Notch pathway is a highly conserved signaling system essential for modulating neurogenesis and promoting astrogenesis. Similarly, the cAMP signaling cascade can promote astrocytic commitment in several cell culture models, such as the C6 glioma cell line. These cells have the capacity to differentiate into oligodendrocytes or astrocytes, characteristics that allow their use as a glial progenitor model. In this context, we explore here the plausible involvement of cAMP in Notch-dependent signal transactions. The exposure of C6 cells to a non-hydrolysable cAMP analogue resulted in a sustained augmentation of Notch activity, as detected by nuclear translocation of its intracellular domain portion (NICD) and transcriptional activity. The cAMP effect is mediated through the activation of the γ-secretase complex, responsible for Notch cleavage and is sensitive to inhibitors of the cAMP-dependent protein kinase, PKA. As expected, Notch cleavage and nuclear translocation resulted in the up-regulation of the mRNA levels of one of its target genes, the transcription factor Hair and enhancer of split 5. Moreover, the glutamate uptake activity, as well as the expression of astrocytic markers such as glial fibrillary acidic protein, S100β protein and GLAST was also enhanced in cAMP-exposed cells. Our results clearly suggest that during the process of C6 astrocytic differentiation, cAMP activates the PKA/γ-secretase/NICD/RBPJ(κ) pathway and Notch1 expression, leading to transcriptional activation of the genes responsible for glial progenitor cell fate decision.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Developmental dependence on NurRE and EboxNeuro for expression of pituitary proopiomelanocortin. 18388149

    Cell-specific expression of the pituitary proopiomelanocortin (POMC) gene depends on the combinatorial action of a large number of DNA-binding transcription factors (TFs). These include general and cell-restricted factors, as well as factors that act as effectors of signaling pathways. We have previously defined in the distal POMC promoter a composite regulatory element that contains targets for basic helix-loop-helix TFs conferring cell specificity and for NGFI-B orphan nuclear receptors that are responsive to CRH signaling and to glucocorticoid negative feedback. These factors act on neighboring regulatory elements, the Ebox(Neuro) and NurRE, respectively. Currently, the Ebox(Neuro) is thought to be the target of NeuroD1 during fetal development, but this factor may not account for activity in the adult pituitary; it is also unknown whether the NurRE and NGFI-B-related factors are active before establishment of the hypothalamic-pituitary portal system. In order to assess the importance of these regulatory elements and their cognate TFs throughout pituitary organogenesis and in the adult, we have assessed the activity of mutant POMC promoters in transgenic mice throughout development. These experiments indicate that the Ebox(Neuro) and cognate basic helix-loop-helix factors are required throughout development and in the adult gland, beyond expression of NeuroD1. Similarly, the data reveal sustained importance of the NurRE and its cognate factors throughout pituitary development. These data contrast the sustained dependence throughout development on the same regulatory elements with the highly dynamic patterns of TF expression and the modulation of their activity in response to signaling pathways.
    Document Type:
    Reference
    Product Catalog Number:
    ABE991
    Product Catalog Name:
    Anti-NeuroD1 Antibody

  • Increased chemotactic migration and growth in heparanase-overexpressing human U251n glioma cells. 18647407

    Heparanase is an endoglycosidase that degrades heparan sulfate, the main polysaccharide constituent of the extracellular matrix (ECM) and basement membrane. Expression of the heparanase gene is associated with the invasion and metastatic potential of a variety of tumor-derived cell types. However, the roles of heparanase in the regulation of gene expression and the subsequent cell function changes other than invasion are not clear. In the current study, we overexpressed the human heparanase gene in a human U251n glioma cell line. We found that heparanase-overexpression significantly increased cell invasion, proliferation, anchorage-independent colony formation and chemotactic migration towards fetal bovine serum (FBS)-supplied medium and stromal cell-derived factor-1 (SDF-1). These phenotypic appearances were accompanied by enhanced protein kinase B (AKT) phosphorylation. Focal adhesion kinase (FAK) and extracellular signal-regulated kinase 1 (ERK1) signaling were not altered by heparanase-overexpression. These results indicate that heparanase has pleiotropic effects on tumor cells.
    Document Type:
    Reference
    Product Catalog Number:
    AB1952
    Product Catalog Name:
    Anti-Integrin beta1 Antibody, Cytosolic

  • A complex choreography of cell movements shapes the vertebrate eye. 22186726

    Optic cup morphogenesis (OCM) generates the basic structure of the vertebrate eye. Although it is commonly depicted as a series of epithelial sheet folding events, this does not represent an empirically supported model. Here, we combine four-dimensional imaging with custom cell tracking software and photoactivatable fluorophore labeling to determine the cellular dynamics underlying OCM in zebrafish. Although cell division contributes to growth, we find it dispensable for eye formation. OCM depends instead on a complex set of cell movements coordinated between the prospective neural retina, retinal pigmented epithelium (RPE) and lens. Optic vesicle evagination persists for longer than expected; cells move in a pinwheel pattern during optic vesicle elongation and retinal precursors involute around the rim of the invaginating optic cup. We identify unanticipated movements, particularly of central and peripheral retina, RPE and lens. From cell tracking data, we generate retina, RPE and lens subdomain fate maps, which reveal novel adjacencies that might determine corresponding developmental signaling events. Finally, we find that similar movements also occur during chick eye morphogenesis, suggesting that the underlying choreography is conserved among vertebrates.
    Document Type:
    Reference
    Product Catalog Number:
    06-570
    Product Catalog Name:
    Anti-phospho-Histone H3 (Ser10) Antibody, Mitosis Marker

  • AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas. 21778190

    Neurofibromatosis type 2 (NF2) is an autosomal-dominant disease that results in the formation of bilateral vestibular schwannomas (VSs) and multiple meningiomas. Treatment options for NF2-associated tumors are limited, and to date, no medical therapies are FDA approved. The ideal chemotherapeutic agent would inhibit both VS and meningiomas simultaneously. The objectives of this study are (1) to test the efficacy of AR42, a novel histone deacetylase inhibitor, to inhibit VS and meningioma growth and (2) to investigate this drug's mechanisms of action. Primary cultures of human VS and meningioma cells were established. Nf2-deficient mouse schwannoma and benign human meningioma Ben-Men-1 cells were also cultured. Cells were treated with AR42, and the drug's effects on proliferation and the cell cycle were analyzed using a methanethiosulfonate assay and flow cytometry, respectively. Human phospho-kinase arrays and Western blots were used to evaluate the effects of AR42 on intracellular signaling. The in vivo efficacy of AR42 was investigated using schwannoma xenografts. Tumor volumes were quantified using high-field, volumetric MRI, and molecular target analysis was performed using immunohistochemistry. AR42 inhibited the growth of primary human VS and Nf2-deficient mouse schwannoma cells with a half maximal inhibitory concentration (IC(50)) of 500 nM and 250-350 nM, respectively. AR42 also inhibited primary meningioma cells and the benign meningioma cell line, Ben-Men-1, with IC(50) values of 1.5 µM and 1.0 µM, respectively. AR42 treatment induced cell-cycle arrest at G(2) and apoptosis in both VS and meningioma cells. Also, AR42 exposure decreased phosphorylated Akt in schwannoma and meningioma cells. In vivo treatment with AR42 inhibited the growth of schwannoma xenografts, induced apoptosis, and decreased Akt activation. The potent growth inhibitory activity of AR42 in schwannoma and meningioma cells suggests that AR42 should be further evaluated as a potential treatment for NF2-associated tumors.
    Document Type:
    Reference
    Product Catalog Number:
    06-599
    Product Catalog Name:
    Anti-acetyl-Histone H3 Antibody

  • MicroRNA-195 plays a tumor-suppressor role in human glioblastoma cells by targeting signaling pathways involved in cellular proliferation and invasion. 22217655

    Accumulating evidence has implicated the deregluation of miRNAs in tumorigenesis. Previous studies have reported that microRNA-195 (miR-195) is markedly down-regulated in human glioblastoma cells, compared with normal brain tissue, but the biological role of miR-195 in glioblastoma development is currently unknown. In this study, we define a tumor-suppressor role for miR-195 in human glioblastoma cells. Over-expression of miR-195 in glioblastoma cell lines robustly arrested cell cycle progression and significantly repressed cellular invasion. We identified E2F3 and CCND3 as functional downstream targets of miR-195 in glioblastoma cells. Through knockdown studies, we demonstrated that E2F3 was the dominant effector of miR-195-mediated cell cycle arrest and that CCND3 was a key mediator of miR-195-induced inhibition of glioblastoma cell invasion. Furthermore, we showed that p27(Kip1) was an important regulator downstream of CCND3 and that the accumulation of p27(Kip1) in the cytoplasm might be responsible for the miR-195-mediated cell invasion inhibition in glioblastoma cells. This work provides evidence for the initial mechanism by which miR-195 negatively regulates both the proliferation and invasion of glioblastoma cells, suggesting that the down-regulation of miR-195 might contribute to the malignant transformation of glioblastoma cells and could be a molecular signature associated with glioblastoma progression.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Reelin controls neuronal positioning by promoting cell-matrix adhesion via inside-out activation of integrin α5β1. 23083738

    Birthdate-dependent neuronal layering is fundamental to neocortical functions. The extracellular protein Reelin is essential for the establishment of the eventual neuronal alignments. Although this Reelin-dependent neuronal layering is mainly established by the final neuronal migration step called "terminal translocation" beneath the marginal zone (MZ), the molecular mechanism underlying the control by Reelin of terminal translocation and layer formation is largely unknown. Here, we show that after Reelin binds to its receptors, it activates integrin α5β1 through the intracellular Dab1-Crk/CrkL-C3G-Rap1 pathway. This intracellular pathway is required for terminal translocation and the activation of Reelin signaling promotes neuronal adhesion to fibronectin through integrin α5β1. Since fibronectin is localized in the MZ, the activated integrin α5β1 then controls terminal translocation, which mediates proper neuronal alignments in the mature cortex. These data indicate that Reelin-dependent activation of neuronal adhesion to the extracellular matrix is crucial for the eventual birth-date-dependent layering of the neocortex.
    Document Type:
    Reference
    Product Catalog Number:
    AB2033
    Product Catalog Name:
    Anti-Fibronectin Antibody

  • Axoplasmic importins enable retrograde injury signaling in lesioned nerve. 14687545

    Axoplasmic proteins containing nuclear localization signals (NLS) signal retrogradely by an unknown mechanism in injured nerve. Here we demonstrate that the importin/karyopherin alpha and beta families underlie this process. We show that importins are found in axons at significant distances from the cell body and that importin beta protein is increased after nerve lesion by local translation of axonal mRNA. This leads to formation of a high-affinity NLS binding complex that traffics retrogradely with the motor protein dynein. Trituration of synthetic NLS peptide at the injury site of axotomized dorsal root ganglion (DRG) neurons delays their regenerative outgrowth, and NLS introduction to sciatic nerve concomitantly with a crush injury suppresses the conditioning lesion induced transition from arborizing to elongating growth in L4/L5 DRG neurons. These data suggest a model whereby lesion-induced upregulation of axonal importin beta may enable retrograde transport of signals that modulate the regeneration of injured neurons.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • The soluble form of the tumor suppressor Lrig1 potently inhibits in vivo glioma growth irrespective of EGF receptor status. 23723255

    Deregulated growth factor signaling is a major driving force in the initiation and progression of glioblastoma. The tumor suppressor and stem cell marker Lrig1 is a negative regulator of the epidermal growth factor receptor (EGFR) family. Here, we addressed the therapeutic potential of the soluble form of Lrig1 (sLrig1) in glioblastoma treatment and the mechanism of sLrig1-induced growth inhibition.With use of encapsulated cells, recombinant sLrig1 was locally delivered in orthotopic glioblastoma xenografts generated from freshly isolated patient tumors. Tumor growth and mouse survival were evaluated. The efficacy of sLrig1 and the affected downstream signaling was studied in vitro and in vivo in glioma cells displaying variable expression of wild-type and/or a constitutively active EGFR mutant (EGFRvIII).Continuous interstitial delivery of sLrig1 in genetically diverse patient-derived glioma xenografts led to strong tumor growth inhibition. Glioma cell proliferation in vitro and tumor growth in vivo were potently inhibited by sLrig1, irrespective of EGFR expression levels. Of importance, tumor growth was also suppressed in EGFRvIII-driven glioma. sLrig1 induced cell cycle arrest without changing total receptor level or phosphorylation. Affected downstream effectors included MAP kinase but not AKT signaling. Of importance, local delivery of sLrig1 into established tumors led to a 32% survival advantage in treated mice.To our knowledge, this is the first report demonstrating that sLrig1 is a potent inhibitor of glioblastoma growth in clinically relevant experimental glioma models and that this effect is largely independent of EGFR status. The potent anti-tumor effect of sLrig1, in combination with cell encapsulation technology for in situ delivery, holds promise for future treatment of glioblastoma.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple