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

Neuronal precursor cells present in dorsal root ganglia (DRG) during early development have been previously shown to differentiate in vitro to neurons, as characterized by morphology, cell surface antigens, and electrophysiological properties (H. Rohrer, S. Henke-Fahle, T. El-Sharkawy, H. D. Lux, and H. Thoenen, 1985, Embo J. 4, 1709-1714). In the present study the conditions necessary for the initial differentiation and long-term survival of these cells were established, and the neurotransmitter phenotype of the newly differentiated neurons was analyzed. Neuronal precursor cells isolated from chick DRG at Embryonic Day 6 (E6) were found to require the presence of a polyornithine substrate coated with either laminin or fibronectin for initial neurite production and long-term survival. Neurons were unable to develop on polyornithine alone or on polyornithine coated with BSA. The survival and neurite outgrowth from neuronal precursor cells was not affected by the presence of nerve growth factor (NGF) during the first 9 hr in culture. NGF also had no effect on the proportion of cells expressing the neuron-specific Q211 antigen. However, after this initial differentiation period the neurons did require the presence of a survival factor. The neurons could be maintained for at least 6 days in culture both in the presence of NGF and in the presence of brain-derived neurotrophic factor (BDNF). At saturating concentrations of both survival factors no additive effects could be observed, indicating a complete overlap of NGF- and BDNF-responsiveness. Although the same proportion of cells survived with either NGF or BDNF during the first 3 days in culture, survival decreased in the presence of BDNF but not in the presence of NGF during the following 3 days in culture. The loss of BDNF responsiveness in vitro was also observed in vivo. After 6 days in culture about 70% of the neurons expressed substance P immunoreactivity, and approximately the same proportion was positive for myelin-associated glycoprotein immunoreactivity. The neurons did not express properties of adrenergic neurons such as tyrosine hydroxylase immunoreactivity or norepinephrine uptake. These findings indicate that the neuronal precursor cells from E6 DRG acquire the same characteristics in vitro as in their normal in vivo environment.
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PMID:Neuronal precursor cells in chick dorsal root ganglia: differentiation and survival in vitro. 245 Jul 97

Ciliary neurotrophic factor (CNTF) influences the levels of choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH) in cultures of dissociated sympathetic neurons from newborn rats. In the presence of CNTF both the total and specific activity of ChAT was increased 7 d after culture by 15- and 18-fold, respectively, as compared to cultures kept in the absence of CNTF. Between 3 and 21 d in culture in the presence of CNTF the total ChAT activity increased by a factor of greater than 100. Immunotitration demonstrated that the elevated ChAT levels were due to an increased number of enzyme molecules. In contrast to the increase in ChAT levels, the total and specific activity levels of TH were decreased by 42 and 36%, respectively, after 7 d in culture. Half-maximal effects for both ChAT increase and TH decrease were obtained at CNTF concentrations of approximately 0.6 ng and maximal levels were reached at 1 ng of CNTF per milliliter of medium. The effect of CNTF on TH and ChAT levels were seen in serum-containing medium as well as in serum-free medium. CNTF was shown to have only a small effect on the long-term survival of rat sympathetic neurons. We therefore concluded that the effects of CNTF on ChAT and TH are not due to selective survival of cells that acquire cholinergic traits in vitro, but are rather due to the induction of cholinergic differentiation of noradrenergic sympathetic neurons.
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PMID:Ciliary neurotrophic factor induces cholinergic differentiation of rat sympathetic neurons in culture. 256 6

Ciliary neurotrophic factor (CNTF) was originally characterized as a survival factor for chick ciliary neurons in vitro. More recently, it was shown to promote the survival of a variety of other neuronal cell types and to affect the differentiation of E7 chick sympathetic neurons by inhibiting their proliferation and by inducing the expression of vasoactive intestinal peptide immunoreactivity (VIP-IR). In cultures of dissociated sympathetic neurons from newborn rats, CNTF induces cholinergic differentiation as shown by increased levels of choline acetyltransferase (ChAT). This increase is paralleled by a reduction of tyrosine hydroxylase (TH) activity. Moreover, CNTF promotes the differentiation of bipotential 02A progenitor cells to type-2-astrocytes in vitro. To help establish which, if any, of these functions CNTF exerts in vivo, it is necessary to determine its primary structure, cellular expression, developmental regulation and localization. The complementary DNA-deduced amino-acid sequence and subsequent expression of cDNA clones covering the entire coding region in HeLa-cells indicate that CNTF is a cytosolic protein. This, together with its regional distribution and its developmental expression, show that CNTF is not a target-derived neurotrophic factor. CNTF thus seems to exhibit neurotrophic and differentiation properties only after becoming available either by cellular lesion or by an unknown release mechanism.
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PMID:Molecular cloning, expression and regional distribution of rat ciliary neurotrophic factor. 259 85

Gene deletion of neurotrophin-3 (NT3) results in severe sensory and sympathetic deficits that are incompatible with postnatal life in mice. We have now addressed the question of whether NT3 plays a role in the postnatal animal. An antiserum specific for NT3 and capable of blocking the survival effect of the factor in vitro has been generated and given to neonatal rats. Antiserum administration during either or both of the first 2 postnatal weeks resulted in a 54-74% reduction in the size of the superior cervical ganglia, reflecting a loss of as many as 80% of all neurons, with a predominant effect on the neuropeptide Y containing subpopulation. The immunoreactivities of NPY, tyrosine hydroxylase, and p75 low affinity NGF receptor in nerve terminals within the mesenteric artery were also reduced, whereas that of the sensory neuron neuropeptide, calcitonin gene related peptide was less affected. These results demonstrate that the majority of sympathetic neurons of the neonatal rat are dependent on endogenous NT3 for their survival at a time when they are also dependent on another survival factor, NGF, thus apparently providing a clear example of a population of neurons requiring for their survival the simultaneous supply of more than one trophic factor.
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PMID:Sympathetic neurons in neonatal rats require endogenous neurotrophin-3 for survival. 747 14

Brain-derived neurotrophic factor (BDNF) has been shown to increase the survival of dopaminergic neurons in rodent mesencephalic cultures. The mRNAs of BDNF and trkB receptor have been found to be expressed in the substantia nigra of rat. In this study, the action of BDNF was studied on the survival and transmitter-specific differentiation of dopaminergic neurons of fetal human CNS aged 9-10-week in vitro. Dopaminergic neuron viability and phenotypic expression were monitored by tyrosine hydroxylase (TH) immunohistochemistry and measurement of dopamine (DA) content with HPLC, respectively. After seven days of treatment with BDNF there were 2.2-fold greater number of TH+ neurons surviving than in untreated cultures. Although very low levels of DA were detectable in human tissue, considerable amounts of DA was found in the culture medium from around 13 days in vitro (DIV), indicating that DA in human fetal tissue tended to be synthesised and released into the incubation medium more readily than from cultured rat fetal tissue during the same period. The content of DA in the BDNF-treated cultures was approximately double that of untreated cultures after 7 days. In rat fetal tissue, the capacity of each TH+ neuron to produce DA was not changed in the BDNF-treated cultures (7 DIV) compared with control cultures, suggesting that BDNF does not up-regulate the production of DA but rather acts to reduce cell death rates. Ciliary neurotrophic factor (CNTF) treatment of rat mesencephalic culture failed to improve the period of survival of fetal dopaminergic neurons and had no effect on the production of DA in cultures.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The response of human and rat fetal ventral mesencephalon in culture to the brain-derived neurotrophic factor treatment. 780 29

Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) have previously been shown to increase the survival and/or differentiation of cholinergic spinal motoneurons in culture. We report here that CNTF and LIF increase choline acetyltransferase (ChAT) activity three- to fourfold in cultures from the ventral mesencephalon (VM) containing cholinergic neurons from cranial motor nuclei and the pedunculopontine nucleus, but decrease tyrosine hydroxylase activity to 50-60% of control values. In contrast, they do not increase cholinergic properties in cultured septal and striatal cholinergic neurons. In order to identify the subpopulations of cholinergic neurons in the mesencephalic cultures responding to CNTF and LIF, embryonic VM was cut into rostral, caudal, central, and laterocaudal portions and cultured separately. CNTF and LIF increased ChAT activity only in the rostral and central VM, which contain cranial motor nuclei, and not in the caudal VM, which contains the rostroventral part of the pedunculopontine nucleus. Together with the previous observations on spinal motoneurons, the present results indicate that only cholinergic motoneurons projecting to peripheral targets, but not cholinergic neurons projecting centrally, may respond to CNTF and LIF by an increase in ChAT activity or by increased neuronal survival.
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PMID:Development of CNS cholinergic neurons in vitro: selective effects of CNTF and LIF on neurons from mesencephalic cranial motor nuclei. 791 Nov 11

Ciliary neurotrophic factor (CNTF) was found to promote the expression of tyrosine hydroxylase (TH) immunoreactivity by cultured noradrenergic neurons from the locus coeruleus (LC) of E18 rat fetuses, but only in the concomitant presence of norepinephrine (NE), their own neurotransmitter. The number of TH-positive cells in LC cultures was shown to decrease by 65% within 3 days and by 75% after 6 days. Treatment with 10 TU/ml human recombinant CNTF together with 1 microM NE was able to fully maintain the initial number of TH-positive neurons for 3 days. This effect, however, was no longer seen after 6 days of continuous exposure. A 24-hr treatment with CNTF/NE was capable of completely restoring the initial number of TH-positive cells, even if its addition was delayed for 2 days. Moreover, when its addition was delayed for 5 days, CNTF/NE restored approximately 80% of the TH-positive neurons that were initially present. These results suggest that the disappearance of TH-positive neurons in LC cultures is not due to their death, but rather to the reduced expression of TH and that the simultaneous exposure to CNTF and NE upregulates TH. Effects on TH-positive cell number were not evoked by CNTF or NE alone. The CNTF/NE effect was dependent on protein synthesis, but was only partially inhibited by RNA synthesis inhibitors, suggesting that both transcription from preexisting mRNA and synthesis of new RNA were stimulated. The effect of CNTF/NE was mediated by alpha 2-adrenoceptors, since it was blocked by alpha 2-antagonists and since alpha 2-agonists were able to substitute for NE. Our results suggest a novel mechanism of regulation of the phenotype of the noradrenergic LC neuron, involving the collaborative influences of CNTF and norepinephrine, their own neurotransmitter.
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PMID:Cooperative effects of ciliary neurotrophic factor and norepinephrine on tyrosine hydroxylase expression in cultured rat locus coeruleus neurons. 809 34

Ciliary neurotrophic factor and dopamine were found to enhance the expression of tyrosine hydroxylase immunoreactivity in cultured neurons from the substantia nigra of 16-day-old rat fetuses. The number of tyrosine hydroxylase-positive cells decreased progressively to approximately 30% by 96 h. Treatment with 5 microM dopamine maintained the tyrosine hydroxylase-positive neurons at 60% for 48 h, but not for longer. Concurrent treatment with 5 microM dopamine and 20 trophic units/ml ciliary neurotrophic factor had a greater impact on tyrosine hydroxylase-positive cells, resulting in the maintenance of 70% of the initial number for up to 72 h, but not beyond that time. When dopamine or dopamine/ciliary neurotrophic factor treatments were applied for 24 h after a 48-h delay, the number of tyrosine hydroxylase-positive cells was restored to 60 and 80%, respectively, but not restoration was observed with 96-h delayed treatments. These results suggest that dopamine and ciliary neurotrophic factor, alone or in combination, are not able to support the survival of tyrosine hydroxylase-positive neurons, but reduce their apparent numerical loss by enhancing the expression of tyrosine hydroxylase. The effects of dopamine, alone or in combination with ciliary neurotrophic factor, were predominantly mediated by D2 receptors, since they were blocked by selective D2 receptor antagonists and since the D2 receptor agonist quinpirole was able to substitute for dopamine. The effects of dopamine and ciliary neurotrophic factor were similar in astroblast-rich and in astroblast-depleted cultures, suggesting that they were not mediated through glial cells. These results extend our previous observations on locus coeruleus cultures, in which the concurrent treatment with ciliary neurotrophic factor and norepinephrine was shown to enhance tyrosine hydroxylase expression (but not survival) of noradrenergic neurons. They also consolidate the view that ciliary neurotrophic factor and the neuron's own transmitter act in convergence and in an autocrine/paracrine mode as regulators of the corresponding neurotransmitter phenotype.
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PMID:Convergent regulation by ciliary neurotrophic factor and dopamine of tyrosine hydroxylase expression in cultures of rat substantia nigra. 809 11

Glial cell line-derived neurotrophic factor was initially identified as a survival factor for developing midbrain dopamine neurons (for reviews, see Refs 17 and 19). Subsequent studies have demonstrated a more wide-spread role for glial cell line-derived neurotrophic factor in the developing and adult CNS. In the adult rat brain, for instance, prior administration of glial cell line-derived neurotrophic factor protects nigrostriatal dopamine neurons from 6-hydroxydopamine-induced damage. When given several weeks after 6-hydroxydopamine injection, glial cell line-derived neurotrophic factor also restores the function of these neurons. Glial cell line-derived neurotrophic factor attenuates excitotoxin-induced cell death in the striatum and hippocampal formation and protective effects of glial cell line-derived neurotrophic factor following axotomy have been reported for spinal motor neurons and basal forebrain cholinergic neurons. These findings suggest that glial cell line-derived neurotrophic factor may be a protective/restorative agent for a diverse population of neurons and imply that it may be a useful therapeutic tool for a variety of neurodegenerative diseases including Parkinson's, Huntington's and Alzheimer's diseases. The potential receptor mediating the pleiotropic effects of glial cell line-derived neurotrophic factor has been characterized only recently as a novel glycosyl-phosphatidylinositol-linked protein, GDNFR-alpha. Because GDNFR-alpha is a cell surface receptor, an additional protein(s) was thought to be involved in the glial cell line-derived neurotrophic factor signalling cascade. The identity of the likely candidate, ret, was inferred initially from indirect evidence. Not only were there remarkable similarities in the distribution of glial cell line-derived neurotrophic factor and the proto-oncogene ret in the developing rat and mouse brain, but also in the phenotype of glial cell line-derived neurotrophic factor knockout mice and mice with ret mutations. Mice with either mutation exhibited pronounced renal and enteric abnormalities, implicating the receptor tyrosine kinase protein product of the ret proto-oncogene as the glial cell line-derived neurotrophic factor signalling protein. More conclusive evidence showing that activation of GDNFR-alpha by glial cell line-derived neurotrophic factor induces phosphorylation of ret has confirmed ret as a signalling protein for glial cell line-derived neurotrophic factor. Preliminary results showing that 6-hydroxydopamine lesions of the substantia nigra markedly reduced ret messenger RNA expression, established its localization to presumably glial cell line-derived neurotrophic factor-responsive dopamine neurons in the nigrostriatal pathway. In contrast, it is not clear whether other glial cell line-derived neurotrophic factor-responsive neurons in the CNS, such as the basal forebrain cholinergic neurons and striatal neurons, also express ret, nor is it evident whether levels of the protein are regulated by disruption of the respective pathways. The present study shows that dense networks of ret immunoreactivity are distributed throughout the nigrostriatal pathway, with lower densities of staining in other brain regions, including the septohippocampal pathway. Following extensive unilateral 6-hydroxydopamine lesions of the medial forebrain bundle, ret immunoreactivity in the substantia nigra and striatum was reduced significantly, to a similar extent as tyrosine hydroxylase immunoreactivity. In contrast, excitotoxic lesions of the striatum, achieved by intrastriatal quinolinic acid injections, resulted in increased ret staining in this brain region. In addition, marked decrements in septal ret immunoreactivity were consequent to complete transections of the fimbria-fornix.
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PMID:ret receptor tyrosine kinase immunoreactivity is altered in glial cell line-derived neurotrophic factor-responsive neurons following lesions of the nigrostriatal and septohippocampal pathways. 925 16

A recombinant adeno-associated virus (rAAV) vector capable of infecting cells and expressing rat glial cell line-derived neurotrophic factor (rGDNF), a putative central nervous system dopaminergic survival factor, under the control of a potent cytomegalovirus (CMV) immediate/early promoter (AAV-MD-rGDNF) was constructed. Two experiments were performed to evaluate the time course of expression of rAAV-mediated GDNF protein expression and to test the vector in an animal model of Parkinson's disease. To evaluate the ability of rAAV-rGDNF to protect nigral dopaminergic neurons in the progressive Sauer and Oertel 6-hydroxydopamine (6-OHDA) lesion model, rats received perinigral injections of either rAAV-rGDNF virus or rAAV-lacZ control virus 3 weeks prior to a striatal 6-OHDA lesion and were sacrificed 4 weeks after 6-OHDA. Cell counts of back-labeled fluorogold-positive neurons in the substantia nigra revealed that rAAV-MD-rGDNF protected a significant number of cells when compared with cell counts of rAAV-CMV-lacZ-injected rats (94% vs. 51%, respectively). In close agreement, 85% of tyrosine hydroxylase-positive cells remained in the nigral rAAV-MD-rGDNF group vs. only 49% in the lacZ group. A separate group of rats were given identical perinigral virus injections and were sacrificed at 3 and 10 weeks after surgery. Nigral GDNF protein expression remained relatively stable over the 10 weeks investigated. These data indicate that the use of rAAV, a noncytopathic viral vector, can promote delivery of functional levels of GDNF in a degenerative model of Parkinson's disease.
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PMID:Midbrain injection of recombinant adeno-associated virus encoding rat glial cell line-derived neurotrophic factor protects nigral neurons in a progressive 6-hydroxydopamine-induced degeneration model of Parkinson's disease in rats. 939 Nov 56


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