EC:1.14.16.2 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.16.2 (tyrosine hydroxylase)
14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adult life span in inbred strains of Drosophila melanogaster (Dm) has been found to be controlled by a few major genes (Hereditas 111:207, 1989; Hereditas 117: 251, 1992). A 77 kDa protein, which we named ju-myo (life-span) protein (JP) and is supposed to be the product of the gene on autosomal locus JmA on adult Dm was shown to have life-span prolonging effect when it was supplied in food. However, the knowledge of its structure and molecular mechanisms by which JP exerts its effects on cells is still unclear. Here we show that JP can exert neurotrophic activities on postmitotic fetal rat neurons isolated from cerebral cortical and dopaminergic neurons isolated from the midbrain: it enhanced survival of MAP2-positive cells and tyrosine hydroxylase immunoreactive neurons by approximately 2-fold over the control group. JP did not increase the density of astrocytes nor expression of glial fibrillary acidic protein (GFAP) in the mesencephalic neuron cultures. Amino acid analysis of JP protein showed that JP is identical to the larval serum protein 2, of which sequence and structure were determined in 1997. Our work provides basis for defining the physiological role of JP at the molecular level and for exploring its potential utility as an alternative approach to study mechanisms of aging.
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PMID:[cDNA cloning of ju-myo protein (JP) and elucidation of the molecular mechanisms by which it exerts neurotrophic effects on neurons]. 1036 26

Cerebral catecholamines and angiotensins are both involved in the regulation of cardiovascular function. Recent in vitro studies have suggested that angiotensin II modulates noradrenergic neurotransmission by controlling both the expression and neuritic trafficking of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. To assess the potential existence of such mechanisms in vivo, we compared TH phenotype ontogeny in the nucleus tractus solitarius (NTS), which is the first central relay of the baroreflex, between control Sprague-Dawley rats and TGR(ASrAOGEN) rats (TG) with glial specific angiotensinogen (AOGEN) depletion. TG displayed a delayed increase in both TH-mRNA and TH protein levels, which sharply rises in the NTS of control rats within the fourth week. The delayed maturation of TH phenotype also affected the presence of TH protein in the neuropil, not only within the NTS region but also within the ventrolateral medulla. This was evidenced by a large decrease in the density of TH-containing neuronal processes in TG at 4 weeks only, without noticeable modification of the labeling of the neuritic marker MAP2, suggesting that neuritic trafficking of TH protein was transiently altered. These results indicate that glial AOGEN is crucial to coordinate within the fourth week the mechanisms driving the maturation of NTS catecholaminergic neurons and suggest that impairment of the central angiotensinergic system early in development can lead to cardiovascular dysfunction related to altered maturation of catecholaminergic neurons located in both the dorsal and the ventrolateral medulla.
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PMID:Delayed maturation of catecholamine phenotype in nucleus tractus solitarius of rats with glial angiotensinogen depletion. 1451 24

Ascorbic acid (AA) has been shown to increase the yield of dopaminergic (DA) neurons derived from basic fibroblast growth factor (bFGF)-expanded mesencephalic precursors. To understand the molecular mechanisms underlying this phenomenon, we used cDNA microarray analysis to examine differential expression of neuronal genes following AA treatment. The putative precursor cells were isolated from E13 rat ventral mesencephalons and expanded in the presence of bFGF. Cells were incubated in mitogen-free media supplemented with 200 microM AA or were left untreated as a control, and total RNA was isolated at different time points (expansion stage and 1, 3, and 6 days after induction of differentiation) and subjected to cDNA microarray analysis. Differentiation was evaluated by Western blot analysis and immunocytochemistry of neuron-specific markers. AA treatment of the mesencephalic precursors increased the expression of neuronal (MAP2) and astrocytic (glial fibrillary acidic protein) markers and the percentage of tyrosine hydroxylase (TH)-positive cells. The microarray analysis revealed that 12 known genes were up-regulated and 20 known genes were down-regulated in expansion-stage AA-treated cells. Six days after the induction of differentiation, AA-treated cells showed up-regulation of 48 known genes and down-regulation of 5 known genes. Our results identified several proteins, such as transferrin, S-100, and somatostatin, as being differentially regulated in AA-treated mesencephalic precursors. This novel result may lead to a better understanding of the molecular mechanisms underlying the AA-induced differentiation of mesencephalic precursors into DA neurons and may form the basis for improved DA neuronal production for treatment of Parkinson's disease patients.
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PMID:Changes of gene expression profiles during neuronal differentiation of central nervous system precursors treated with ascorbic acid. 1537 4

We examined the neurochemical phenotype of striatal neurons expressing tyrosine hydroxylase (TH) mRNA to determine if they form a distinct class of neurons within the human striatum. Double in situ hybridization (ISH) and immunohistochemical (IHC) procedures were used to know if TH mRNA-positive striatal neurons express molecular markers of mature neurons (MAP2 and NeuN), dopaminergic neurons (DAT and Nurr1) or immature neurons (TuJ1). All TH mRNA-labeled neurons were found to express NeuN, DAT and Nurr1, whereas about 80% of them exhibited MAP2, confirming their neuronal and dopaminergic nature. Only about 30% of TH mRNA-labeled neurons expressed TuJ1, suggesting that this ectopic dopaminergic neuronal population is principally composed of mature neurons. The same double ISH/IHC approach was then used to know if these dopamine neurons display markers of well-established classes of striatal projection neurons (GAD65 and calbindin) or local circuit neurons (GAD65, calretinin, somatostatin and parvalbumin). Virtually all TH-labeled neurons expressed GAD65 mRNA, about 30% of them exhibited calretinin, but none stained for the other striatal neuron markers. These results suggest that the majority of TH-positive neurons intrinsic to the human striatum belong to a distinct subpopulation of striatal interneurons characterized by their ability to produce dopamine and GABA.
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PMID:Neurochemical characterization of dopaminergic neurons in human striatum. 1597 Apr 54

The adult subventricular zone (SVZ) supports a population of cells that display the hallmarks of stem cells: they are self-renewing and multipotent-capable of generating neurons, oligodendrocytes, and astrocytes. In vivo, these adult neural stem cells (aNSCs) are fated primarily for a gamma-amino butyric acid (GABA)-ergic lineage of olfactory bulb interneurons, a small subpopulation of which is dopaminergic. Here, we investigate the plasticity of aNSCs in vitro, in particular, their ability to generate a specific neuronal lineage, midbrain dopamine neurons. Previous work using mouse embryonic stem (ES) cells showed that introduction of early developmental inductive cues, sonic hedgehog (SHH) and fibroblast growth factor-8 (FGF-8), directed ES cell-derived neuroepithelial cells to generate midbrain dopaminergic neurons, those lost in Parkinson's disease. Placing aNSCs under similar culture conditions, immunocytochemistry and RT-PCR analysis revealed early dopaminergic neuron specification. However, aNSC-derived neurons remained morphologically immature, exhibiting concurrent nestin and tyrosine hydroxylase (TH) expression, with cell death occurring in the final differentiation stage. High-performance liquid chromatography (HPLC) analysis revealed that while aNSC-derived neurons released dopamine, release was not significantly increased following depolarization with K+. In contrast, ES cell-generated TH+ neurons expressed the mature markers MAP2 and NeuN and showed K+-evoked release of dopamine. Reduced culture time of aNSC-derived nestin+ progenitors in FGF-2-containing medium improved survival of TH+ neurons. However, these neurons exhibited characteristics of forebrain dopamine neurons and also expressed low levels of midbrain transcription factors. Together, our data indicate that when presented with in vitro conditions that promote midbrain-specific dopamine neuron specification, aNSCs instead generate forebrain-like dopamine neurons, demonstrating their restricted and prescribed nature.
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PMID:In vitro generation of dopaminergic neurons from adult subventricular zone neural progenitor cells. 1824 23

Freshly isolated fetal midbrain neural precursor cells (NPCs) that maintain the potential to differentiate into dopamine (DA) neurons represent a valuable source for cell therapy in Parkinson's disease. However, it is poorly understood why midbrain NPCs lose their dopaminergic differentiation potential after long-term culture. Here we report that human fetal midbrain NPCs can be extensively proliferated with fibroblast growth factor 2 (FGF-2), epidermal growth factor (EGF), and leukemia inhibitory factor (LIF) and efficiently differentiated into tyrosine hydroxylase-immunoreactive (TH-ir) neurons. We tested differentiation conditions including the use of low oxygen, ascorbic acid, and prolonged in vitro differentiation time which resulted in a 10-fold increase in the number of MAP2-positive neurons (up to 40-50% of total cells as compared to controls). Under these conditions TH-ir cells constituted 4.3+/-0.5% of the neuronal population and displayed immature morphologies. Notably, the use of brain-derived neurotrophic factor (BDNF) further increased the proportion of TH-ir neurons (up to 15% of total neurons). In contrast to previous reports, our findings demonstrate that long-term expanded fetal NPCs can generate TH-expressing cells under the appropriate culture conditions and without genetic manipulations.
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PMID:Combined use of BDNF, ascorbic acid, low oxygen, and prolonged differentiation time generates tyrosine hydroxylase-expressing neurons after long-term in vitro expansion of human fetal midbrain precursor cells. 1865 26

We assessed the presence of degenerating neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) of parkinsonian monkeys. For this purpose, we used two histological markers of cellular death, Fluoro Jade B (FJB) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL). Eight monkeys were subacutelly treated with four to six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injections (1-1.5 mg/kg, cumulative dose) and sacrificed 1 week and 11 months after last MPTP injection. Eight additional monkeys were chronically exposed to MPTP (4.5-15.3 mg/kg, cumulative dose) and sacrificed 6-35 months after last MPTP dose. Three intact monkeys served as controls. The number of tyrosine hydroxylase (TH)- and TUNEL-positive cells was quantified in SNpc and VTA and colocalization of FJB-positive and TUNEL-positive cells with neuronal (TH, NeuN, MAP2) and glial markers (human ferritin, GFAP) assessed on doubly labelled tissue sections. Only MPTP monkeys with 1-week survival displayed few doubly FJB-TH-labelled cells. Both groups of subacute MPTP monkeys, but not chronic MPTP monkeys, showed a significant increased number of TUNEL-positive cells in SNpc. TUNEL-positive cells exhibited morphological features and histological markers indicative of glial cells, whereas TUNEL/NeuN or TUNEL/MAP-2 colocalization was not observed. Our results indicate that MPTP treatment produced a nonapoptotic cell death of dopaminergic cells and the activation of the apoptotic cascade in glial cells. More importantly, we failed to demonstrate the existence of a delayed neurodegenerative process in the dopaminergic neurons after concluding MPTP injection thus, casting doubt on the validity of the "progressive model" created by repeated MPTP administration to monkeys.
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PMID:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure fails to produce delayed degeneration of substantia nigra neurons in monkeys. 1879 85

SH-SY5Y neuroblastoma cells, a model for studying neuronal differentiation, are able to differentiate into either cholinergic or dopaminergic/adrenergic phenotypes depending on media conditions. Using this system, we asked whether guanosine (Guo) or guanosine-5'-triphosphate (GTP) are able to drive differentiation towards one particular phenotype. Differentiation was determined by evaluating the frequency of cells bearing neurites and assessing neurite length after exposure to different concentrations of Guo or GTP for different durations. After 6 days, 0.3 mM Guo or GTP induced a significant increase in the number of cells bearing neurites and increased neurite length. Western blot analyses confirmed that purines induced differentiation; cells exposed to purines showed increases in the levels of GAP43, MAP2, and tyrosine hydroxylase. Proliferation assays and cytofluorimetric analyses indicated a significant anti-proliferative effect of purines, and a concentration-dependent accumulation of cells in S-phase, starting after 24 h of purine exposure and extending for up to 6 days. A transcriptional profile analysis using gene arrays showed that an up-regulation of cyclin E2/cdk2 evident after 24 h was responsible for S-phase entry, and a concurrent down-regulation of cell-cycle progression-promoting cyclin B1/B2 prevented S-phase exit. In addition, patch-clamp recordings revealed that 0.3 mM Guo or GTP, after 6 day incubation, significantly decreased Na(+) currents. In conclusion, we showed Guo- and GTP-induced cell-cycle arrest in neuroblastoma cells and suggest that this makes these cells more responsive to differentiation processes that favor the dopaminergic/adrenergic phenotype.
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PMID:Extracellular guanosine and GTP promote expression of differentiation markers and induce S-phase cell-cycle arrest in human SH-SY5Y neuroblastoma cells. 1911 4

Previously, we have reported that glioblastoma (GBM) cells can be differentiated into cells showing neuronal, glial and non-neural (mesenchymal) phenotypes. Before the differentiation the GBM cells co-expressed GFAP, CD44, Beta III tubulin, MAP2, Vimentin, Nestin and SOX-2, whereas during the exposure to a neural differentiation medium the differentiation process was arrested at the early stages and the GBM cells presented features of four phenotypes: multi-lineage, non-neural (mesenchymal), intermediate of neuronal cells and glial cells. Currently, we decided to check if changes in expression of: TH (tyrosine hydroxylase, marker of catecholaminergic cells) and GABA (neurotransmitter of GABAergic neurons) and markers of oligodendrocytic cells (O4, CNP) occur during the exposure of GBM cells to the differentiation medium. After exposure to the PDGF alpha and thyroid hormones (oligodendrocytic differentiation medium 10-30 days) features of oligodendrocytic differentiation were presented by 0.2-2.4% of analyzed cells. During the prolonged neural differentiation (GDNF, bFGF 20-30 days) only few cells showed expression of GABA. Moreover, in our cell cultures, there were not cells expressing markers of catecholaminergic neurons - TH. Our work confirmed that the neuronal differentiation of GBM was inhibited at the stage of the neuronal intermediate phenotype. Moreover, we showed that the oligodendrocytic differentiation of GBM cells is very inefficient.
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PMID:Imperfect oligodendrocytic and neuronal differentiation of glioblastoma cells. 2038 8

Amniotic fluid is known to yield a number of cell types which are multipotent, ethically derived, genetically stable, easily grown, expanded and possess favourable immunogenicity, which has resulted in an increasing interest for use in various neuronal disorders such as Parkinson's disease. The neuronal potential of cells derived from the adherent fraction of amniotic fluid, routinely taken by amniocentesis, are least explored. The aim of the present study was to investigate the capacity of these cells for neuronal and dopaminergic differentiation using in vitro differentiation protocols with canonical inductive factors not previously tested. To do this, samples derived from multiple donors were grown under four conditions: standard serum-containing media, NB (neurobasal) media designed specifically for propagation and maintenance of neuronal cells, NB media with addition of retinoic acid and BDNF (brain-derived neurotrophic factor) for NI (neuronal induction), and NB media with addition of FGF8 (fibroblast growth factor-8) and Shh (sonic hedgehog) after NI. Our results showed the presence of multiple neuronal markers after growth in serum-containing medium [TUJ1, MAP2, NF-M, TH (tyrosine hydroxylase)], which was significantly up-regulated after serum withdrawal in NB medium alone with induction of NeuN (neuronal nuclei) and NSE (neuron-specific enolase). NI and DA.I (dopaminergic induction) was accompanied by further increases in expression and a distinct transition to a sustained neuronal morphology. Western blot analysis confirmed increasing TH expression and NURR1, expressed in base serum-containing media, found to be down-regulated after induction. In conclusion, these cells possess a highly favourable base neuronal and dopaminergic prepotential, which may easily be accentuated by standard induction protocols.
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PMID:In vitro differentiation of human amniotic fluid-derived cells: augmentation towards a neuronal dopaminergic phenotype. 2038 19

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