Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Bone morphogenetic proteins (BMPs) are a family of growth differentiation factors which induce bone formation from mesenchymal cells. These proteins are members of the transforming growth factor-beta super-family. The expression of BMPs in the nervous system as well as in other tissues has been reported. In this study, we show that the presence of BMP-2 resulted in a dose-dependent increase in the number of tyrosine hydroxylase-immunoreactive ventral mesencephalic cells after 7 days in serum-free medium cultures. A maximal response was elicited at 10 ng/mL. BMP-2 also increased the number of primary neurites and branch points as well as the length of the longest neurite in a dose-dependent manner, with a maximal effect at 1 ng/mL. In contrast, BMP-2 did not modify the number or the function of GABAergic neurons. On the other hand, we observed stimulation of proliferation and morphological changes in glial cells (astrocytes become more fibrous shaped) in the presence of a high BMP-2 concentration (100 ng/mL), but not with lower doses, suggesting that the neurotrophic effect in dopaminergic neurons is not mediated by astroglial cells. This is consistent with the fact that the BMP-2 effect on dopaminergic neurons was observed even when the cultures were treated with alpha-aminoadipic acid to exclude the presence of glial cells. In summary, our data indicate that BMP-2 is a potent neurotrophic factor for ventral mesencephalic dopaminergic cells in culture.
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PMID:Bone morphogenetic protein-2 promotes dissociated effects on the number and differentiation of cultured ventral mesencephalic dopaminergic neurons. 1002 64

Both glial cell line-derived neurotrophic factor (GDNF) and its recently discovered congener, neurturin (NTN), have been shown to exert neuroprotective effects on lesioned nigral dopamine (DA) neurons when administered at the level of the substantia nigra. In the present study, we have explored the relative in vivo potency of these two neurotrophic factors using two alternative routes of administration, into the striatum or the lateral ventricle, which may be more relevant in a clinical setting. In rats subjected to an intrastriatal (IS) 6-hydroxydopamine (6-OHDA) lesion, GDNF and NTN were injected every third day for 3 weeks starting on the day after the 6-OHDA injection. GDNF provided almost complete (90-92%) protection of the lesioned nigral DA neurons after both IS and intracerebroventricular (ICV) administration. NTN, by contrast, was only partially effective after IS injection (72% sparing) and totally ineffective after ICV injection. Although the trophic factor injections protected the nigral neurons from lesion-induced cell death, the level of expression of the phenotypic marker, tyrosine hydroxylase (TH), was markedly reduced in the rescued cell bodies. The extent of 6-OHDA-induced DA denervation in the striatum was unaffected by both types of treatment; consistent with this observation, the high rate of amphetamine-induced turning seen in the lesioned control animals was unaltered by either GDNF or NTN treatment. In the GDNF-treated animals, and to a lesser extent also after IS NTN treatment, prominent axonal sprouting was observed within the globus pallidus, at the level where the lesioned nigrostriatal axons are known to end at the time of onset of the neurotrophic factor treatment. The results show that GDNF is highly effective as a neuroprotective and axon growth-stimulating agent in the IS 6-OHDA lesion model after both IS and ICV administration. The lower efficacy of NTN after IS, and particularly ICV, administration may be explained by the poor solubility and diffusion properties at neutral pH.
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PMID:Protection and regeneration of nigral dopaminergic neurons by neurturin or GDNF in a partial lesion model of Parkinson's disease after administration into the striatum or the lateral ventricle. 1021 8

The sympathetic, parasympathetic and enteric ganglia are the main components of the peripheral autonomic nervous system, and are all derived from the neural crest. The factors needed for these structures to develop include the transcription factor Mash1, the glial-derived neurotrophic factor GNDF and its receptor subunits, and the neuregulin signalling system, each of which is essential for the differentiation and survival of subsets of autonomic neurons. Here we show that all autonomic ganglia fail to form properly and degenerate in mice lacking the homeodomain transcription factor Phox2b, as do the three cranial sensory ganglia that are part of the autonomic reflex circuits. In the anlagen of the enteric nervous system and the sympathetic ganglia, Phox2b is needed for the expression of the GDNF-receptor subunit Ret and for maintaining Mash1 expression. Mutant ganglionic anlagen also fail to switch on the genes that encode two enzymes needed for the biosynthesis of the neurotransmitter noradrenaline, dopamine-beta-hydroxylase and tyrosine hydroxylase, demonstrating that Phox2b regulates the noradrenergic phenotype in vertebrates.
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PMID:The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. 1036 May 75

Glial cell line-derived neurotrophic factor (GDNF) is a potent and specific neurotrophic factor for dopaminergic neurons. GDNF has been previously shown to protect dopaminergic neurons from lesion-induced degeneration in vivo. In this study we investigated the effect of GDNF on 6-hydroxydopamine (6-OHDA)-treated dopaminergic neurons in vitro. In dissociated cultures of embryonic rat mesencephalon, 6-OHDA exhibited a dose-dependent cytotoxicity on tyrosine hydroxylase (TH)-immunoreactive neurons. After pre-treatment with GDNF, however, 6-OHDA-induced loss of dopaminergic neurons was effectively reduced. It has been shown recently that GDNF signals through the receptor tyrosine kinase Ret and the GDNF receptor-alpha (GFR-alpha). By RT-PCR, we found both Ret- and GFR-alpha-genes to be expressed in the cultured mesencephalic cells. We propose that the neuroprotective effect of GDNF on 6-OHDA-treated dopaminergic neurons in vitro is most likely mediated by functional Ret receptor signaling pathways.
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PMID:Glial cell line-derived neurotrophic factor protects dopaminergic neurons from 6-hydroxydopamine toxicity in vitro. 1045 61

Sympathetic neurons comprise a population of postmitotic, tyrosine hydroxylase expressing cells whose survival is dependent upon nerve growth factor (NGF) both in vivo and in vitro. However, during development precursors to rat sympathetic neurons in the thoracolumbar region are not responsive to NGF because they lack the signal transducing NGF receptor, trkA. We have previously shown that acquisition of trkA expression is sufficient to confer a functional response to NGF. Here we describe four subpopulations of thoracolumbar sympathetic neuroblasts which are mitotically active and unresponsive to NGF at E13.5 of rat gestation, but differ based upon their neurotrophic responsiveness in vitro. The survival in culture of the largest sympathetic subpopulation is mediated by neurotrophin-3 (NT-3) or glial-derived neurotrophic factor (GDNF), whereas the cell survival of two smaller subpopulations of neuroblasts are mediated by either solely GDNF or solely NT-3. Finally, we identify a subpopulation of sympathetic neuroblasts in the thoracolumbar region whose survival, exit from the cell cycle, induction of trkA expression, and consequent acquisition of NGF responsiveness in culture appear to be neurotrophin independent and cell autonomous. These subpopulations reflect the diversity of neurotrophic actions that occur in the proper development of sympathetic neurons.
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PMID:Subpopulations of rat B2(+) neuroblasts exhibit differential neurotrophin responsiveness during sympathetic development. 1065 76

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for mesencephalic dopaminergic neurons. Subpopulations of these neurons express the calcium-binding proteins calbindin (CB) and calretinin (CR). Understanding the specific effects of GDNF on these neurons is important for the development of an optimal cell replacement therapy for Parkinson's disease. To investigate the effects of GDNF on the morphological complexity of mesencephalic tyrosine hydroxylase (TH)-immunoreactive (-ir), CB-ir, and CR-ir neurons, dissociated cultures of embryonic (E14) rat ventral mesencephalon were prepared. Chronic administration of GDNF (10 ng/ml) for 7 days promoted the survival of TH-ir and CB-ir neurons but did not alter the density of CR-ir neurons. Total fiber length/neuron and number of branching points/neuron of CB-ir and CR-ir cells were significantly increased after GDNF treatment (2x for CB-ir cells and 1.4x and 1.7x, respectively, for CR-ir cells), which resulted in a significantly larger size of neurite field/neuron (2.9x and 1.5x for CB-ir and CR-ir neurons, respectively). The number of primary neurites/neuron of CB-ir neurons was found to be 1.5x larger, while no difference could be detected for CR-ir cells. Assessment of the effects of GDNF on TH-ir neurons unveiled a similar outcome with an increased total fiber length/neuron (1.5x), an increased number of primary neurites/neuron (1.6x), and a twofold larger size of neurite field/neuron. In conclusion, our findings recognize GDNF as a neurotrophic factor that stimulates the morphological differentiation of ventral mesencephalic CB-ir and CR-ir neurons.
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PMID:Glial cell line-derived neurotrophic factor stimulates the morphological differentiation of cultured ventral mesencephalic calbindin- and calretinin-expressing neurons. 1087 17

A wealth of evidence indicates that insulin-like growth factor (IGF-1) is involved in neurotransmitter release, synaptic plasticity, morphogenesis and regulation of gene expression. RT-PCR and immunocytochemical-based techniques revealed that IGF-1 and its receptor are highly expressed by different neuronal elements of the spinal cord lumbar enlargement. Accordingly, the present study intended to examine lumbospinal monoamine dynamics in the context of the neurotrophic factor IGF-1. Spinal release of norepinephrine (NE) represented by 3-methoxy-4-hydroxyphenylglycol (MHPG)/NE ratio was enhanced by IGF-1. This action of IGF-1 was associated with a similar increase in both tyrosine hydroxylase (TH) immunoreactivity and the level of its mRNA. In contrast, neuronal contents of serotonin and its metabolite 5-hydroxyindoleacetic acid in IGF-1-treated animals remained at control level. Genistein, a tyrosine kinase inhibitor, which by itself had no effect on NE metabolism, abolished the induction effect of IGF-1 on TH and MHPG/NE ratio. Our results suggest that IGF-1 augments the lumbospinal noradrenergic system by an intracellular mechanism involving a receptor-linked tyrosine kinase. The physiological consequences of the IGF-1 actions are discussed in terms of neuroprotection and nociception.
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PMID:Insulin-like growth factor 1-induced alterations in lumbospinal monoamine dynamics. 1089 49

The use of fetal astrocytes for gene delivery into brains with neurodegenerative diseases has been suggested. Therefore, the effects of neurotransmitters in the brain on such cells are of interest. The presence of D1(D1A) receptors and the effect of dopamine on a fetal human astrocyte cell line (SVG cells) in vitro were examined. SVG cells expressed D1(D(1A)), but not D5(D1B) receptors, as shown by RT-PCR. Exposure to dopamine, apomorphine, and the specific D1 agonist, SKF-38393, increased glial-derived neurotrophic factor production of SVG cells, as well as intracellular free calcium. Exposure to the specific D1 antagonist, SCH 23390, blocked these effects. Thus, if implanted into a brain region rich in dopamine, or if transfected with the tyrosine hydroxylase gene, fetal astrocytes may serve as paracrine/autocrine cells capable of supplying critical growth factors to diseased brain tissue.
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PMID:Dopamine increases glial cell line-derived neurotrophic factor in human fetal astrocytes. 1118 May 11

Brain-derived neurotrophic factor (BDNF; 50 ng/ml), dopamine (DA; 10 microM) and forskolin (Fsk; 10 microM) have previously been shown by this and other laboratories to induce the tyrosine hydroxylase (TH) enzyme in foetal human and rat cerebral cortex during specified sensitive developmental periods. In the present study, these findings were extended for human and rat cells by showing that the induced TH+ cells also produce dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). In addition to this, TH induction and DA plus DOPAC production was observed in foetal human and rat cerebral cortex by using glial-cell derived neurotrophic factor (GDNF) in place of BDNF. The degree of induction by GDNF (1-10 ng/ml) was similar to that produced by BDNF and did not increase further when the two neurotrophic factors were used together. The time-course of induction in human cultures was followed: GDNF was found to cause a more rapid induction process than BDNF during the first 2 weeks. However the degree of induction after 3 weeks was the same for both neurotrophic factors. Inhibitors of transcription (actinomycin D) or of translation (cycloheximide) eliminated all the increase in DA+DOPAC contents elicited by these compounds, indicating that de novo transcription and translation were required for increased expression of the TH and other related enzymes. The intracellular pathways by which these molecules exert this dopaminergic phenotype induction effect are discussed. This study indicates a new source of dopaminergic brain tissue for use as transplants to neurosurgically treat Parkinson's disease patients.
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PMID:Parallel induction of the formation of dopamine and its metabolites with induction of tyrosine hydroxylase expression in foetal rat and human cerebral cortical cells by brain-derived neurotrophic factor and glial-cell derived neurotrophic factor. 1133 98

Previous studies have demonstrated that either the neurotrophin glial-derived neurotrophic factor (GDNF) or the antiapoptotic peptide Bcl-2 delivered into striatum by a viral vector protects dopaminergic neurons of the substantia nigra in vivo from degeneration induced by the administration of the neurotoxin 6-hydroxydopamine (6-OHDA). In this study we used recombinant, replication-incompetent, genomic herpes simplex virus-based vectors to deliver the genes coding for Bcl-2 and GDNF into rat substantia nigra (SN) 1 week prior to 6-OHDA injection into the striatum. Vector-mediated expression of either Bcl-2 or GDNF alone each resulted in a doubling in cell survival as measured by retrograde labeling with fluorogold (FG) and a 50% increase in tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the lesioned SN compared to the unlesioned side. Gene transfer of Bcl-2 and GDNF were equivalent in this effect. Coadministration of the Bcl-2-expressing vector with the GDNF-expressing vector improved the survival of lesioned SN neurons as measured by FG labeling by 33% and by the expression of TH-IR by 15%. These results suggest that the two factors delivered together act in an additive fashion to improve DA cell survival in the face of 6-OHDA toxicity.
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PMID:Bcl-2 and GDNF delivered by HSV-mediated gene transfer act additively to protect dopaminergic neurons from 6-OHDA-induced degeneration. 1135 38


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