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)

Neurotrophins influence the epigenetic shaping of the vertebrate nervous system by regulating neuronal numbers during development and synaptic plasticity. Here we attempt to determine whether these growth factors can also regulate neurotransmitter plasticity. As a model system we used the selection between noradrenergic and cholinergic neurotransmission by paravertebral sympathetic neurons. Developing sympathetic neurons express the neurotrophin receptors TrkA and TrkC, two highly related receptor tyrosine kinases. Whereas the TrkA ligand nerve growth factor (NGF) has long been known to regulate both the survival and the expression of noradrenergic traits in sympathetic neurons, the role of TrkC and of its ligand neurotrophin-3 (NT3) has remained unclear. We found that TrkC expression in the avian sympathetic chain overlaps substantially with that of choline acetyltransferase. In sympathetic chain explants, transcripts of the cholinergic marker genes choline acetyltransferase and vasoactive intestinal polypeptide were strongly enriched in the presence of NT3 compared with NGF, whereas the noradrenergic markers tyrosine hydroxylase and norepinephrine transporter were reduced. The transcription factor chicken achaete scute homolog 1 was coexpressed with cholinergic markers. The effects of NT3 are reversed and antagonized by NGF. They are independent of neuronal survival and developmentally regulated. These results suggest a role for NT3 as a differentiation factor for cholinergic neurons and establish a link between neurotrophins and neurotransmitter plasticity.
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PMID:Neurotrophin-3 promotes the cholinergic differentiation of sympathetic neurons. 1093 39

Mature nodose and petrosal ganglia neurons (placodally derived afferent neurons of the vagal and glossopharyngeal nerves) contain TrkA and TrkC, and transport specific neurotrophins [nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4)]. This study evaluated neurotrophin influences on the presence of neuropeptides and/or neurotransmitter enzymes in these visceral sensory neurons. NGF, NT-3 and NT-4 (10-100 ng/ml) were applied (5 days) to dissociated, enriched, cultures of mature nodose/petrosal ganglia neurons, and the neurons processed for tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and neurofilament (NF-200) immunocytochemistry. Addition of NGF to nodose/petrosal ganglia neuron-enriched cultures significantly increased the number of TH-immunoreactive (ir) neurons, decreased the number of VIP-ir neurons in the cultures, and did not affect the numbers of CGRP-ir neurons. The addition of an NGF neutralizing antibody attenuated the effects of NGF on TH and VIP-ir neurons. NT-3 increased the number of VIP-ir neurons in the nodose/petrosal ganglia cultures and did not alter the numbers of TH-, or CGRP-ir neurons. The addition of an NT-3 neutralizing antibody attenuated the effects of NT-3 on VIP-ir neurons. NT-4 had no significant effects on the numbers of TH, VIP and CGRP-ir neurons. The absence of neurotrophin-induced changes in the numbers of NF-200-ir neurons in culture showed the lack of neurotrophin-mediated changes in survival of mature vagal afferent neurons. These data demonstrate that specific neurotrophins influence the numbers of neurons labeled for specific neurochemicals in nodose/petrosal ganglia cultures. These data, coupled with previous evidence for the presence of TrkA and TrkC mRNA and of the retrograde transport of NGF and NT-3, suggest important roles for NGF and NT-3 in the maintenance of transmitter phenotype of these mature visceral afferent neurons.
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PMID:Neurotrophins alter the numbers of neurotransmitter-ir mature vagal/glossopharyngeal visceral afferent neurons in vitro. 1108 4

The classical view of norepinephrine transporter (NET) function is the re-uptake of released norepinephrine (NE) by mature sympathetic neurons and noradrenergic neurons of the locus ceruleus (LC; [1-3]). In this report we review previous data and present new results that show that NET is expressed in the young embryo in a wide range of neuronal and non-neuronal tissues and that NET has additional functions during embryonic development. Sympathetic neurons are derived from neural crest stem cells. Fibroblast growth factor-2 (FGF-2), neurotrophin-3 (NT-3) and transforming growth factor-beta1 (TGF-beta1) regulate NET expression in cultured quail neural crest cells by causing an increase in NET mRNA levels. They also promote NET function in both neural crest cells and presumptive noradrenergic cells of the LC. The growth factors are synthesized by the neural crest cells and therefore are likely to have autocrine function. In a subsequent stage of development, NE transport regulates differentiation of noradrenergic neurons in the peripheral nervous system and the LC by promoting expression of tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH). Conversely, uptake inhibitors, such as the tricyclic antidepressant, desipramine, and the drug of abuse, cocaine, inhibit noradrenergic differentiation in both tissues. Taken together, our data indicate that NET is expressed early in embryonic development, NE transport is involved in regulating expression of the noradrenergic phenotype in the peripheral and central nervous systems, and norepinephrine uptake inhibitors can disturb noradrenergic cell differentiation in the sympathetic ganglion (SG) and LC.
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PMID:Norepinephrine transporter expression and function in noradrenergic cell differentiation. 1110 37

Somatic symptoms and aversion of opiate withdrawal, regulated by noradrenergic signaling, were attenuated in mice with a CNS-wide conditional ablation of neurotrophin-3. This occurred in conjunction with altered cAMP-mediated excitation and reduced upregulation of tyrosine hydroxylase in A6 (locus coeruleus) without loss of neurons. Transgene-derived NT-3 expressed by noradrenergic neurons of conditional mutants restored opiate withdrawal symptoms. Endogenous NT-3 expression, strikingly absent in noradrenergic neurons of postnatal and adult brain, is present in afferent sources of the dorsal medulla and is upregulated after chronic morphine exposure in noradrenergic projection areas of the ventral forebrain. NT-3 expressed by non-catecholaminergic neurons may modulate opiate withdrawal and noradrenergic signalling.
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PMID:Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal. 1152 74

Little is known on the influence of epigenetic factors in the developing hypothalamus, a region particularly involved in neuroendocrine regulation and rich in neuropeptides. The present study evaluated the effects of neurotrophins and neuronal activity on neuronal differentiation in hypothalamic cultures sampled from either arcuate or anterior periventricular regions of 17-day-old Sprague-Dawley fetuses. Expression of neuropeptides, tyrosine hydroxylase, neurotrophins and neurotrophin receptors was tested on young (6 days in vitro, DIV) and more mature (14 DIV) cultured neurons by multiple reverse transcription polymerase chain reaction on single cells. In parallel, spontaneous postsynaptic currents were recorded as an index of neuronal connectivity. Neurotrophin-3 (NT3) was expressed in a much larger population of neurons than brain-derived neurotrophic factor (BDNF) at both culture times. At 6 DIV, synaptic currents were scarce and expression of the neurotrophin receptors trkB and trkC was found in a small proportion of neurons only. These parameters increased markedly between 6 and 14 DIV, and also upon addition of neurotrophins. The most striking consequence of arcuate neuron maturation in vitro between 6 and 14 DIV was a marked phenotypic specification affecting somatostatin, neuropeptide Y and pro-opiomelanocortin, the three major neuropeptides expressed in the cultures. NT3, but not BDNF, was able to reproduce maturation-related phenotypic specification in 6 DIV arcuate cultures. Maturation-dependent phenotypic specification was less marked in periventricular cultures; in that case BDNF, not NT3 had a slight effect on phenotype specification. It is concluded that NT3 plays a selective role in phenotypic specification of neuropeptides in the arcuate region, whereas other maturation parameters (neurotrophin receptor expression and/or synaptogenesis) can be potentiated by either neurotrophin in both structures.
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PMID:The neurotrophins NT3 and BDNF induce selective specification of neuropeptide coexpression and neuronal connectivity in arcuate and periventricular hypothalamic neurons in vitro. 1181 35

The locus coeruleus (LC) is a major target of several neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. However, very little is known of the trophic requirements of LC neurons. In the present work, we have studied the biological activity of neurotrophic factors from different families in E15 primary cultures of LC neurons. In agreement with previous results, neurotrophin-3 (NT-3) and also glial cell line- derived neurotrophic factor (GDNF) increased the number of embryonic LC noradrenergic neurons in the presence of serum. In serum-free conditions, none of the factors tested, including NT-3, GDNF, neurturin, basic fibroblast growth factor (bFGF), or bone morphogenetic protein-2 (BMP-2), promoted the survival of tyrosine hydroxylase (TH)-immunoreactive neurons at 6 days in vitro. However, when BMP-2 was coadministered with any of these factors the number of LC TH-positive neurons increased twofold. Similar results were obtained by cotreatment of LC neurons with forskolin and NT-3, bFGF, or BMP-2. The strongest effect (a fourfold increase in the number of TH-positive cells) was induced by cotreatment with forskolin, BMP-2, and GDNF. Thus, our results show that LC neurons require multiple factors for their survival and development, and suggest that activation of LC neurons by bone morphogenetic proteins and cAMP plays a decisive role in conferring noradrenergic neuron responsiveness to several trophic factors.
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PMID:BMP-2 and cAMP elevation confer locus coeruleus neurons responsiveness to multiple neurotrophic factors. 1189 64

Effects of three neurotrophins, i.e., nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3, on the expression of four neurotransmitter-synthesizing enzymes, i.e. choline acetyltransferase (ChAT), tyrosine hydroxylase (TH), dopamine beta hydroxylase (DBH), and glutamate decarboxylase 65 were investigated in cultured mouse neural stem cells. All three neurotrophins enhanced the mRNA expression of ChAT, TH, or DBH of the cells caused to differentiate by the removal of fibroblast growth factor (FGF)-2 from the culture medium, and increased the protein and mRNA levels of ChAT and TH of even the undifferentiated proliferating neural stem cells due to the presence of FGF-2. These results demonstrate that neurotrophins stimulate the synthesis of ChAT and TH of the neural stem cells prior to neuronal differentiation, and suggest that neurotrophins may play roles in the commitment to neuronal cells and choice of specific neurotransmitter phenotypes in early stages of neurogenesis.
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PMID:Neurotrophins facilitate synthesis of choline acetyltransferase and tyrosine hydroxylase in cultured mouse neural stem cells independently of their neuronal differentiation. 1263 95

We recently found that human amniotic epithelial (HAE) cells secrete biologically active neurotrophins such as brain-derived neurotrophic factor and neurotrophin-3, both of which exhibit trophic activities on dopamine (DA) neurons. The present study explored whether implantation of HAE cells can be a possible means to deliver trophic factors into the brain to prevent the death of DA neurons in a rat model of Parkinson's disease. We first investigated the ability of HAE cells to produce factors capable of promoting DA cell survival in vitro, and then tested whether HAE cell grafts survive and prevent the death of nigral DA neurons in rats with 6-hydroxydopamine lesions. A treatment with conditioned medium derived from HAE cell cultures enhanced the survival of tyrosine hydroxylase (TH)-immunopositive DA cells in serum-free cultures. The conditioned medium also protected the morphological integrity of TH-positive neurons against toxic insult with 6-hydroxydopamine. HAE cells were grafted into the midbrain of immunosuppressed rats. The rats were then subjected to a unilateral nigrostriatal lesion induced by intrastriatal infusions of 6-hydroxydopamine. HAE cell transplants were found to survive without evidence for overgrowth 2 weeks postgrafting. The number of nigral DA cells, detected with either TH-immunohistochemistry or retrograde labelling with fluorogold, was significantly increased in rats given the grafts as compared to that in control animals without the grafts. The results indicate that HAE cells produce diffusible molecules that can enhance the survival of DA neurons. Although the factors that contribute to the currently observed effects remain to be fully determined, implantation of HAE cells could be a viable strategy to counteract the loss of DA neurons in Parkinson's disease.
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PMID:Implantation of human amniotic epithelial cells prevents the degeneration of nigral dopamine neurons in rats with 6-hydroxydopamine lesions. 1286 58

Exogenous administration of various neurotrophic factors has been shown to protect neurons in animal model of Parkinson's disease (PD). Several attempts are being made to search a tissue source simultaneously expressing many of these neurotrophic factors. Carotid body (CB) contains oxygen-sensitive glomus cells rich in dopamine (DA) and expresses glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor and neurotrophin-3. We have attempted to study the functional restoration following co-transplantation of CB cells and ventral mesencephalic cells (VMC) in a 6-hydroxydopamine-lesioned rat model of PD. A significant recovery (p < 0.001) in d-amphetamine-induced circling behavior (80%) and spontaneous locomotor activity (85%) was evident in co-transplanted animals at 12 weeks post-transplantation as compared to lesioned animals. Similarly, a significant (p < 0.001) restoration was observed in DA-D(2) receptor binding (77%), striatal DA (87%) and 3,4-dihydroxyphenylacetic acid (DOPAC) (85%) levels and nigral DA (75%) and DOPAC (74%) levels. Functional recovery was accompanied by tyrosine hydroxylase (TH) expression and quantification of TH-positive cells by image analysis revealed a significant restoration in TH-immunoreactive (IR) fiber density in striatum, as well as TH-IR neurons in substantia nigra pars compacta in co-transplanted animals over VMC-transplanted animals. The result suggests that co-transplantation of CB cells along with VMC provides better and long-term functional restoration in the rat model of PD, possibly by supporting the survival of newly grafted cells as well as remaining host DA neurons.
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PMID:Co-transplantation of carotid body and ventral mesencephalic cells as an alternative approach towards functional restoration in 6-hydroxydopamine-lesioned rats: implications for Parkinson's disease. 1544 61

The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) have been shown to promote survival and differentiation of midbrain dopaminergic (DAergic) neurons in vitro and in vivo. This is consistent with their expression and that of their cognate receptors, trkB and trkC, in the nigrostriatal system. Degeneration of DAergic neurons of the substantia nigra and alpha-synuclein-positive aggregates in the remaining substantia nigra (SN) neurons are hallmarks of Parkinson's disease (PD). Reduced expression of BDNF has been reported in the SN from PD patients. Moreover, mutations in the BDNF gene have been found to play a role in the development of familial PD. We show now that haploinsufficiencies of the neurotrophin receptors trkB and/or trkC cause a reduction in numbers of SN neurons in aged (21-23 month old) mice, which is accompanied by a reduced density in striatal tyrosine hydroxylase immunoreactive (TH-ir) fibers. These aged mutant mice, in contrast to wild-type littermates, display an accumulation of alpha-synuclein in the remaining TH-positive neurons of the SN. We conclude that impairment in trkB and/or trkC signaling induces a phenotype in the aged SN, which includes two hallmarks of PD, losses of TH positive neurons and axons along with massive neuronal deposits of alpha-synuclein.
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PMID:Haploinsufficiency for trkB and trkC receptors induces cell loss and accumulation of alpha-synuclein in the substantia nigra. 1603 97


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