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  • 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.
    Tipo de documento:
    Referencia
    Referencia del producto:
    ABE991
    Nombre del producto:
    Anti-NeuroD1 Antibody

  • Pool-specific regulation of motor neuron survival by neurotrophic support. 21813676

    The precise control of motor neuron (MN) death and survival following initial innervation of skeletal muscle targets is a key step in sculpting a functional motor system, but how this is regulated at the level of individual motor pools remains unclear. Hepatocyte growth factor (HGF) and its receptor Met play key developmental roles in both muscle and MNs. We generated mice (termed "Nes-Met") in which met is inactivated from midembryonic stages onward in the CNS only. Adult animals showed motor behavioral defects suggestive of impaired innervation of pectoral muscles. Correspondingly, in neonatal spinal cords of Nes-Met mutants, we observed death of a discrete population of pea3-expressing MNs at brachial levels. Axonal tracing using pea3 reporter mice revealed a novel target muscle of pea3-expressing MNs: the pectoralis minor muscle. In Nes-Met mice, the pectoralis minor pool initially innervated its target muscle, but required HGF/Met for survival, hence for proper maintenance of muscle innervation. In contrast, HGF/Met was dispensable for the survival of neighboring Met-expressing MN pools, despite its earlier functions for their specification and axon growth. Our results demonstrate the exquisite degree to which outcomes of signaling by receptor tyrosine kinases are regulated on a cell-by-cell basis. They also provide a model for one way in which the multiplicity of neurotrophic factors may allow for regulation of MN numbers in a pool-specific manner.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AB1987
    Nombre del producto:
    Anti-Neurofilament M (145 kDa) Antibody, CT

  • Antisense peptide nucleic acid targeting GluR3 delays disease onset and progression in the SOD1 G93A mouse model of familial ALS. 15264227

    Glutamate excitotoxicity is strongly implicated as a major contributing factor in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Excitotoxicity results from elevated intracellular calcium ion (Ca(2+)) levels, which in turn recruit cell death signaling pathways. Recent evidence suggests that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit (GluR) stoichiometry is a dominant factor leading to excess Ca(2+) loading in neurodegeneration. In particular, the Ca(2+) permeable glutamate receptor subunit 3 (GluR3) has been implicated in several neurologic conditions such as bipolar disorder and epilepsy. Recent proteomic analysis within our group on the copper zinc superoxide dismutase (SOD1)(G93A) transgenic mouse model of familial ALS (FALS) reveals a potentially deleterious upregulation of GluR3 in spinal cord compared to that in wild-type littermates. Based on this finding we designed a 12mer antisense peptide nucleic acid (PNA) directed against GluR3. This sequence significantly reduced levels of GluR3 protein and protected neuroblastoma x spinal cord (NSC-34) cells against death induced by the AMPA receptor-specific agonist (S)-5-fluorowillardiine. We subsequently treated SOD1(G93A) mice thrice weekly with intraperitoneal injections of the antisense PNA (2.5 mg/kg) commencing at postnatal day 50. Mice treated with the antisense sequence had significantly extended survival compared to mice injected with a nonsense sequence. Western blot analysis, however, did not reveal a significant reduction in GluR3 protein levels in whole extracts of the lumbar spinal cord. These results suggest that interference with the GluR3 component of the AMPA receptor assembly may be a novel strategy for controlling excitotoxic destruction of motor neurons and may lead to new therapeutic opportunities for the treatment of human ALS.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AB5849
    Nombre del producto:
    Anti-Glutamate Receptor 1 Antibody, phosphoSer 845

  • Disrupted transforming growth factor-beta signaling in spinal and bulbar muscular atrophy. 20410122

    Spinal and bulbar muscular atrophy (SBMA) is a late-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract in androgen receptor (AR). Although it is commonly held that the pathogenic polyglutamine proteins accumulate in neurons and thereby induce transcriptional dysregulation, the downstream molecular events have remained elusive. Here, we examined whether TGF-beta signaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2/3, a key step in TGF-beta signaling, is suppressed in the spinal motor neurons of male transgenic mice carrying the mutant human AR. A similar finding was also observed in the motor neurons, but not in Purkinje cells, of SBMA patients. The pathogenic AR, the causative protein of SBMA, inhibits the transcription of TGF-beta receptor type II (TbetaRII) via abnormal interactions with NF-Y and p300/CBP-associated factor. Furthermore, overexpression of TbetaRII dampens polyglutamine-induced cytotoxicity in a neuroblastoma cell line expressing the pathogenic AR. The present study thus indicates that disruption of TGF-beta due to the transcriptional dysregulation of TbetaRII is associated with polyglutamine-induced motor neuron damage in SBMA.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • Alternative pre-mRNA splicing governs expression of a conserved acidic transactivation domain in myocyte enhancer factor 2 factors of striated muscle and brain. 15834131

    Myocyte enhancer factor 2 (MEF2) transcription factors play pivotal roles in striated muscle, neuron, and lymphocyte gene expression and are targets of stress- and calcium-mediated signaling. All MEF2 gene products have a common DNA binding and dimerization domain, but MEF2 transcripts are alternatively spliced among coding exons to produce splicing isoforms. In vertebrate MEF2A, -C, and -D, a splice versus no-splice option gives forms that include or exclude a short domain that we designate beta. We show that mRNAs containing beta are expressed predominantly in striated muscle and brain and that splicing to include beta is induced during myocyte differentiation. MEF2 beta+ isoforms are more robust than beta- forms in activating MEF2-responsive reporters despite similar expression levels. One-hybrid transcription assays using Gal4-MEF2 fusions show similar distinctions in the transactivation produced by beta+ versus beta- isoforms in all cell types tested, including myocytes. beta function is position-independent and exists in all MEF2 splicing variant contexts. The activity is not due to cis effects on MEF2 DNA binding or dimerization nor are established transcription factor or coactivator interactions involved. Each MEF2 beta domain contains multiple acidic residues, mutation of which abolishes function. Despite a location between the p38 MAPK docking domain and Thr phosphoacceptors of MEF2A and MEF2C, inclusion of beta does not influence responses of these factors to this signaling pathway. Thus, a conserved pattern of alternative splicing in vertebrate MEF2 genes generates an acidic activation domain in MEF2 proteins selectively in tissues where MEF2 target genes are highly expressed.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB1501R
    Nombre del producto:
    Anti-Actin Antibody,clone C4

  • Phosphorylation and alternative pre-mRNA splicing converge to regulate myocyte enhancer factor 2C activity. 15340086

    Myocyte enhancer factor 2 (MEF2) transcription factors play pivotal roles in cardiac, muscle, and neuron gene expression. All products of MEF2 genes have a common amino-terminal DNA binding and dimerization domain, but the four vertebrate MEF2 gene transcripts are alternatively spliced among coding exons to produce splicing isoforms. In MEF2C alone, alternative splice acceptors in the last exon give forms that include or exclude a short domain that we designate gamma. We show that MEF2C is expressed exclusively as gamma- isoforms in heart tissue and predominantly as gamma- in other adult tissues and in differentiating myocytes. MEF2C gamma- isoforms are much more robust than gamma+ forms in activating MEF2-responsive reporters in transfected fibroblasts despite indistinguishable expression levels, and they better synergize with MyoD in promoting myogenic conversion. One-hybrid transcription assays using Gal4-MEF2C fusions give similar distinctions between gamma- and gamma+ isoforms in all cell types tested, including myocytes. Cis effects of gamma on MEF2C DNA binding, dimerization, protein stability, or response to CaM or p38 mitogen-activated protein kinase signaling are not apparent, and the isolated gamma domain represses transcription when fused to Gal4. One phosphoserine residue is present within the gamma domain according to tandem mass spectrometry, and mutation of this residue abolishes gamma-mediated transrepression. A similar activity is present in the constitutive gamma domain and serine phosphoacceptor of MEF2A. Our findings indicate that gamma functions autonomously as a phosphoserine-dependent transrepressor to downregulate transactivation function of MEF2 factors and that alternative splicing and serine phosphorylation converge to provide complex combinatorial control of MEF2C activity.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB1501R
    Nombre del producto:
    Anti-Actin Antibody,clone C4

  • A direct fate exclusion mechanism by Sonic hedgehog-regulated transcriptional repressors. 26293298

    Sonic hedgehog (Shh) signaling patterns the vertebrate spinal cord by activating a group of transcriptional repressors in distinct neural progenitors of somatic motor neuron and interneuron subtypes. To identify the action of this network, we performed a genome-wide analysis of the regulatory actions of three key ventral determinants in mammalian neural tube patterning: Nkx2.2, Nkx6.1 and Olig2. Previous studies have demonstrated that each factor acts predominantly as a transcriptional repressor, at least in part, to inhibit alternative progenitor fate choices. Here, we reveal broad and direct repression of multiple alternative fates as a general mechanism of repressor action. Additionally, the repressor network targets multiple Shh signaling components providing negative feedback to ongoing Shh signaling. Analysis of chromatin organization around Nkx2.2-, Nkx6.1- and Olig2-bound regions, together with co-analysis of engagement of the transcriptional activator Sox2, indicate that repressors bind to, and probably modulate the action of, neural enhancers. Together, the data suggest a model for neural progenitor specification downstream of Shh signaling, in which Nkx2.2 and Olig2 direct repression of alternative neural progenitor fate determinants, an action augmented by the overlapping activity of Nkx6.1 in each cell type. Integration of repressor and activator inputs, notably activator inputs mediated by Sox2, is probably a key mechanism in achieving cell type-specific transcriptional outcomes in mammalian neural progenitor fate specification.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AB9610
    Nombre del producto:
    Anti-Olig-2 Antibody

  • HuD interacts with survival motor neuron protein and can rescue spinal muscular atrophy-like neuronal defects. 21088113

    Spinal muscular atrophy is an autosomal-recessive neuromuscular disease caused by disruption of the survival of motor neuron (SMN) gene, which promotes cytoplasmic assembly of the splicing core machinery. It remains unclear how a deficiency in SMN results in a disorder leading to selective degeneration of lower motor neurons. We report here that SMN interacts with RNA-binding protein HuD in neurites of motorneuron-derived MN-1 cells. This interaction is mediated through the Tudor domain of SMN and, importantly, naturally occurring Tudor mutations found in patients with severe spinal muscular atrophy (SMA) completely abrogate the interaction, underscoring its relevance to the disease process. We also characterized a regulatory pathway involving coactivator-associated arginine methyltransferase 1 (CARM1) and HuD. Specifically, we show that CARM1 expression is rapidly downregulated, at the protein level, following induction of differentiation through retinoid and neurotrophic signaling. Using purified proteins, we demonstrate that methylation of HuD by CARM1 reduces its interaction with the p21(cip1/waf1) mRNA, showing that CARM1 can directly influence RNA-binding activity. We further demonstrate that this CARM1-dependent regulatory switch mainly controls the activity of HuD in promoting cell-cycle exit, whereas the interaction between HuD and SMN is required for proper recruitment of HuD and its mRNA targets in neuronal RNA granules. Finally, we were able to rescue SMA-like defects in a hypomorphic Smn knockdown MN-1 cell line through overexpression of HuD. Together, these findings extend our understanding of specific role(s) of SMN in motor neurons and provide crucial insights into potential new avenues for SMA therapeutic strategies.
    Tipo de documento:
    Referencia
    Referencia del producto:
    07-214
    Nombre del producto:
    Anti-dimethyl-Histone H3 (Arg17) Antibody

  • Hyaluronan-CD44 pathway regulates orientation of mitotic spindle in normal epithelial cells. 18513329

    Orientation of mitotic spindle and cell division axis can impact normal physiological processes, including epithelial tissue branching and neuron generation by asymmetric cell division. Microtubule dynamics and its interaction with cortical proteins regulate the orientation of mitotic spindle axis. However, the nature of extracellular signals that control proper orientation of mitotic spindle axis is largely unclear. Here, we show that signals from two distinct surface contact, bi-surface-contact, sites are required for the orientation of mitotic spindle axis in normal epithelial cells. We identified apical and basal surface-membrane as required bi-surface-contact sites. We showed that high molecular weight (HMW) hyaluronan (HA)-CD44 signaling from the apical surface-membrane regulated the orientation of mitotic spindle axis to align parallel to the basal extracellular matrix (ECM). The same effect was achieved by fibronectin-integrin alphavbeta6 signaling from the basal surface-membrane or by inhibition of ROCK activity. On the contrary, HMW HA-CD44 signaling from the basal surface-membrane regulated the orientation of mitotic spindle axis to align oblique-perpendicular to the basal ECM. We also found that microtubule dynamics is required for HMW HA-CD44 mediated regulation of mitotic spindle orientation. Our findings thus provide a novel mechanism for the regulation of mitotic spindle orientation.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB1957
    Nombre del producto:
    Anti-Integrin β3 Antibody, clone 25E11

  • Bone morphogenetic protein regulation of enteric neuronal phenotypic diversity: relationship to timing of cell cycle exit. 18537141

    The effects of bone morphogenetic protein (BMP) signaling on enteric neuron development were examined in transgenic mice overexpressing either the BMP inhibitor, noggin, or BMP4 under control of the neuron specific enolase (NSE) promoter. Noggin antagonism of BMP signaling increased total numbers of enteric neurons and those of subpopulations derived from precursors that exit the cell cycle early in neurogenesis (serotonin, calretinin, calbindin). In contrast, noggin overexpression decreased numbers of neurons derived from precursors that exit the cell cycle late (gamma-aminobutyric acid, tyrosine hydroxylase [TH], dopamine transporter, calcitonin gene-related peptide, TrkC). The numbers of TH- and TrkC-expressing neurons were increased by overexpression of BMP4. These observations are consistent with the idea that phenotypic expression in the enteric nervous system (ENS) is determined, in part, by the number of proliferative divisions neuronal precursors undergo before their terminal mitosis. BMP signaling may thus regulate enteric neuronal phenotypic diversity by promoting the exit of precursors from the cell cycle. BMP2 increased the numbers of TH- and TrkC-expressing neurons developing in vitro from immunoselected enteric crest-derived precursors; BMP signaling may thus also specify or promote the development of dopaminergic TrkC/NT-3-dependent neurons. The developmental defects in the ENS of noggin-overexpressing mice caused a relatively mild disturbance of motility (irregular rapid transit and increased stool frequency, weight, and water content). Although the function of the gut thus displays a remarkable tolerance for ENS defects, subtle functional abnormalities in motility or secretion may arise when ENS defects short of aganglionosis occur during development.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo