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)

NGF is a neurotrophic protein that promotes the survival, growth, and differentiation of developing sympathetic neurons. To directly determine the effects of different concentrations of NGF on neuronal gene expression, we examined mRNAs encoding the p75 low-affinity NGF (LNGF) receptor, T alpha 1 alpha-tubulin (T alpha 1), and tyrosine hydroxylase (TH) in pure cultures of rat sympathetic neurons from postnatal day 1 superior cervical ganglia. Studies of the timecourse of gene expression during 2 wk in culture indicated that a 5-d incubation period would be optimal for the concentration-effect studies. Analysis of RNA isolated from neurons cultured in 2-200 ng/ml 2.5S NGF for 5 d revealed that, as the NGF concentration increased, neurons expressed correspondingly increased levels of all three mRNAs. Both LNGF receptor and TH mRNAs increased seven-fold, and T alpha 1 mRNA increased four-fold in neurons cultured in 200 versus 10 ng/ml NGF. In contrast, T26 alpha-tubulin mRNA, which is constitutively expressed, did not alter as a function of NGF concentration. When neurons were initially cultured in 10 ng/ml NGF for 5 d, and then 200 ng/ml NGF was added, LNGF receptor, T alpha 1, and TH mRNAs all increased within 48 h. The timecourse of induction differed: T alpha 1 mRNA was maximal by 5 h, whereas LNGF receptor and TH mRNAs first began to increase at 12 h after the NGF increase. These experiments show that NGF regulates expression of a subset of mRNAs important to neuronal growth and differentiation over a broad concentration range, suggesting that the effects of NGF may be mediated by more than just a single receptor operating at one fixed affinity. These results also suggest a mechanism for coupling neuronal synthesis of axonal proteins to increases in size of the innervated target territory during growth of the organism.
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PMID:Concentration-dependent regulation of neuronal gene expression by nerve growth factor. 134 50

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

The ovary of humans and nonhuman primates is innervated by sympathetic and sensory neurons of the peripheral nervous system. Recent studies demonstrated that the density of the sympathetic innervation to the rhesus monkey ovary is developmentally regulated, with adult density being attained around the time of puberty. In the present study, we used an immunocytochemical approach to obtain insights into the cell-cell signaling mechanisms that may contribute to the functional maintenance of this innervation. Because sympathetic neurons of the peripheral nervous system require target-derived neurotropins for their survival and function, experiments were conducted to determine if one of the receptors recognized by neurotropins is expressed in fibers innervating the primate ovary. A monoclonal antibody to the human low-affinity nerve growth factor (NGF) receptor, termed p75 NGFR because of its molecular weight, demonstrated the presence of this receptor in nerve fibers innervating the ovarian vasculature, interstitial tissue, and developing follicles of the gland. In addition, as shown in rodents, p75 NGFR immunoreactivity was detected in nonneuronal, endocrine cells of the ovary, specifically the thecal cell layer of developing follicles. Unexpectedly, however, the monkey ovary was also found to contain a network of small p75 NGFR immunoreactive cells distributed throughout the ovarian medulla and cortex. These cells, identified as such by confocal microscopy, had a neural-like appearance and displayed both neurofilament and neuron-specific enolase immunoreactivity. They appeared to be densely interconnected and were seen innervating the ovarian vasculature, the thecal cell layer of follicles, and, occasionally, primordial follicles. Double immunohistochemical procedures demonstrated that a subpopulation of these intraovarian, p75 NGFR-bearing neuron-like cells are catecholaminergic, as determined by their immunoreactivity to antibodies to tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis. RNA blot hybridization revealed the presence of p75 NGFR messenger RNA in the monkey ovary, thus demonstrating the ability of the gland to synthesize the receptors. These results demonstrate that the primate ovary contains an intrinsic network of neuron-like cells. Because such a neuronal network has not been detected in rodents or other non-primate species, it would appear that its presence in the primate ovary may have evolutionary significance.
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PMID:The primate ovary contains a population of catecholaminergic neuron-like cells expressing nerve growth factor receptors. 758 34

The irreversible mitochondrial toxin 3-nitropropionic acid (3-NPA) is a specific inhibitor of succinate dehydrogenase. We performed stereotaxic unilateral injections of 3-NPA into the nigrostriatal dopaminergic pathway in rats in order to examine its specific effects on the dopamine system. The 3-NPA-treated rats displayed unidirectional apomorphineinduced rotations, suggesting that 3-NPA selectively damages dopaminergic neurons when injected into the nigrostriatal pathway. In situ hybridization 7 weeks postinjection indicated a decrease in tyrosine hydroxylase (TH) mRNA to 30% of the noninjected side in the substantia nigra pars compacta (P < 0.05) and decreased to 62% of the noninjected side in the ventral tegmental area (VTA) (nonsignificant) of 3-NPA-lesioned rats. The number of TH mRNA positive cells showed statistically significant decreases in substantia nigra and VTA (P < 0.001) within the lesioned side. In contrast, expression of mRNAs encoding choline acetyltransferase, p75 low-affinity NGF receptor, neurotrophin tyrosine kinase receptors Trk and TrkB, and brain-derived neurotrophic factor showed neuronal sparing in several other regions of the brain. The results suggest that the nigrostriatal dopaminergic system might be selectively vulnerable to 3-NPA and demonstrate that it is possible to employ 3-NPA in a model of partial lesion of the nigrostriatal dopaminergic system resembling early stages of Parkinson's disease.
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PMID:Specific lesions in the extrapyramidal system of the rat brain induced by 3-nitropropionic acid (3-NPA). 772 Aug 19

Hypothalamic neurons control a variety of important hormonal and behavioral functions. Little is known, however, about the neurotrophic factors that these neurons may require for survival and/or maintenance of their differentiated functions. We conducted experiments to examine this issue, utilizing a combination of immunohistochemical, in situ hybridization and cell culture approaches. We found that the low affinity receptor for nerve growth factor (p75 NGFR) is present in small subsets of hypothalamic peptidergic neurons identified as such by their content of galanin, luteinizing hormone-releasing hormone (LHRH) and vasointestinal peptide (VIP). More prominently, however, examination of hypothalamic dopaminergic (DA) neurons for the presence of p75 NGFR-like immunoreactivity revealed that the receptor was present on tyrosine hydroxylase (TH)-positive neurons of the zona incerta and periventricular region, but not on neuroendocrine DA neurons of the tuberoinfundibular region. In situ hybridization experiments using a p75 NGFR cRNA confirmed this distribution. Regardless of the presence or absence of p75 NGFR, neither DA group expresses trkA mRNA, indicating that these two major hypothalamic subsets of DNA neurons are NGF-insensitive. A substantial fraction of TH mRNA-positive cells in the zona incerta expresses trkB mRNA, which encodes the receptor for brain derived neurotrophic factor (BDNF); in turn BDNF supports the in vitro survival of hypothalamic TH neurons bearing p75-NGFR, suggesting that BDNF is trophic for DNA neurons of the zona incerta. In contrast, tuberoinfundibular DA neurons do not express trkB mRNA, but some have trkC mRNA, which encodes the receptor for neurotrophin-3 (NT-3). The in vitro survival of TH neurons devoid of p75-NGFR is supported by NT-3, implying that NT-3 may be trophic for a subset of tuberoinfundibular DA neurons. These results suggest that, in spite of expressing an identical neurotransmitter phenotype, anatomically and functionally segregated DA neurons of the neurodendocrine brain are sustained by different neurotrophic factors.
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PMID:Neurotrophins and the neuroendocrine brain: different neurotrophins sustain anatomically and functionally segregated subsets of hypothalamic dopaminergic neurons. 779 Sep 7

Sympathetic nerve terminals on blood vessels within the dorsal root ganglia sprout after sciatic nerve lesions in the rat. The mechanism underlying this phenomenon is not clear, but might be predicted to involve nerve growth factor or its homologs because these factors are known to trigger collateral sprouting of undamaged sympathetic noradrenergic terminals. We have found that sciatic nerve lesions lead to a decreased expression of neuronal p75, the low-affinity receptor for the neurotrophins, but an increased expression of glial p75 in ipsilateral dorsal root ganglia. Intriguingly, the increased expression of p75 was found primarily in association with glia surrounding large-diameter neurons, which are those associated with the noradrenergic sprouts. A smaller but significant glial response was also found in contralateral ganglia. The glial response in ipsilateral ganglia could be mimicked by ventral, but not dorsal, root transection. The dorsal root lesion-induced glial responses in contralateral ganglia were greater than those induced by ventral root or sciatic nerve lesions. Combined lesions of dorsal root and either ventral root or sciatic nerve did not prevent the glial responses of ipsilateral ganglia, suggesting that a peripheral signal is involved. Colocalization studies indicate that tyrosine hydroxylase-immunoreactive nerve sprouts were associated with p75-immunoreactive glial cells. Thus, increased glial synthesis of p75 might provide an explanation for the abnormal growth of sympathetic fibers in dorsal root ganglia after peripheral nerve injury.
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PMID:Differential expression of the p75 nerve growth factor receptor in glia and neurons of the rat dorsal root ganglia after peripheral nerve transection. 862 21

Ribonuclease protection measurements revealed decreases of 26% in p75 neurotrophin receptor mRNA and 30% in trkA mRNA in superior cervical ganglia (SCG) of aged Long-Evans rats. These declines were not related to the presence of a spatial memory impairment, whose presence is known to strongly predict increased hypothalamic-pituitary-adrenal axis activity in these aged animals. A similar decrease with age was observed in p75, but not cyclophilin mRNA levels in SCG from F-344 inbred rats. In situ hybridization with paired sections from mature and aged F-344 rats revealed a 25% decline in the mean neuronal labeling index (LI) for p75 mRNA. In other paired sections, mean trkA LI decreased 16%, tyrosine hydroxylase (TH) LI increased 74% and cyclophilin LI did not change. Neuronal hypertrophy, p75 decreases and TH increases all occurred to a greatest extent in intermediate-sized neurons, resembling those innervating the pineal and cerebral vessels. In contrast to other SCG targets, this innervation is known to decline nearly 50% with aging. Retrograde tracer/in situ hybridization studies will be required to establish whether decreased p75 represents a marker for selective axonal regression and also to determine the significance of increased TH and neuronal hypertrophy.
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PMID:Neurotrophin receptor and tyrosine hydroxylase gene expression in aged sympathetic neurons. 898 34

To examine the cellular mechanisms whereby distally derived growth factors regulate nuclear responses in neurons, we have utilized compartmented cultures of sympathetic neurons to examine the regulation of two nerve growth factor (NGF)-inducible genes, tyrosine hydroxylase (TH) and p75 neurotrophin receptor (p75NTR). These studies demonstrate that NGF can signal retrogradely to mediate the induction of TH and p75NTR mRNAs. However, quantitative differences occurred as a function of the spatial localization of NGF exposure; application of NGF to cell bodies and proximal axons elicited peak levels of neuronal gene expression that were two- to threefold higher than when NGF was applied to distal axons alone. Furthermore, neurons responding maximally to NGF on distal axons were still able to respond to NGF administered to cell bodies and proximal axons. Biochemical analysis indicated that this difference in responsiveness was not due to differences in the number of TrkA/NGF receptors in the two compartments. Thus, although NGF signals retrogradely to mediate nuclear responses, the magnitude of these responses differs as a function of the spatial location of the activated NGF receptor:ligand complex. Moreover, these data suggest that neurons may be able to respond to a second cellular source of neurotrophins, even when target-derived neurotrophins are not limiting.
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PMID:Spatial regulation of neuronal gene expression in response to nerve growth factor. 914 78

The impact of the nerve growth factor (NGF) family of neurotrophins and their receptors was examined on the cutaneous innervation in the mystacial pads of mice. Ten sets of unmyelinated and thinly myelinated sensory and autonomic innervation were evaluated that terminated in the epidermis, upper dermis, and upper part of the intervibrissal hair follicles. Mystacial pads were analyzed from newborn to 4-week-old mice that had homozygous functional deletions of the genes for NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), tyrosine kinase (trk) A, trkB, trkC, or p75. Mystacial pads were also analyzed in adult transgenic mice that had overproduction of NGF, BDNF, or NT-3 driven by a keratin promoter gene. The innervation was revealed by using immunofluorescence and immunocytochemistry with antibodies for protein gene product (PGP) 9.5, calcitonin gene-related product (CGRP), substance P (SP), galanin (GAL), neuropeptide Y (NPY), tyrosine hydroxylase (TH), and a neurofilament protein. The cumulative results indicated that NGF/trkA signaling plays a major role in the outgrowth and proliferation of sensory axons, whereas NT-3/ trkA signaling plays a major role in the formation of sensory endings. TrkC is also essential for the development of three sets of trkA-dependent sensory innervation that coexpress CGRP, SP, and GAL. Another set of sensory innervation that only coexpressed CGRP and SP was solely dependent upon NGF and trkA. Surprisingly, most sets of trkA-dependent sensory innervation are suppressed by trkB perhaps interacting with p75. BDNF and NT-4 appear to mediate this suppressing effect in the upper dermis and NT-4 in the epidermis. In contrast to sensory innervation, sympathetic innervation to the necks of intervibrissal hair follicles depends upon NGF/trkA signaling interacting with p75 for both the axon outgrowth and ending formation. Although NT-3/trkA signaling is essential for the full complement of sympathetic neurons, NT-3 is detrimental to the formation of sympathetic terminations to the necks of hair follicles. TrkB signaling mediated by BDNF but not NT-4 also suppresses these sympathetic terminations. One sparse set of innervation, perhaps parasympathetic, terminating at the necks of hair follicles is dependent solely upon NT-3 and trkC. Taken together, our results indicate that the innervation of the epidermis, upper dermis, and the upper portion of hair follicles is regulated by a competitive balance between promoting and suppressing effects of the various neurotrophins.
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PMID:Differential dependency of unmyelinated and A delta epidermal and upper dermal innervation on neurotrophins, trk receptors, and p75LNGFR. 964 Mar 32

Nerve growth factor (NGF) regulates the expression of the glycoprotein L1 among neural cell populations. The purpose of this investigation was to determine whether NGF equally affects the immunolocalization of L1 on both sympathetic and sensory axons, and whether the functional expression of the p75 neurotrophin receptor (p75NTR) is required for the immunodetection of this glycoprotein on peripheral axons. Two lines of transgenic mice overexpressing NGF among glial cells were used in this study: (1) one line of mice possessing two normal alleles for p75NTR, and (2) another line of mice possessing two mutated alleles for p75NTR. In both types of animals, sensory axons stained immunohistochemically for calcitonin gene-related peptide and sympathetic axons stained immunohistochemically for tyrosine hydroxylase invaded the deep white matter portions of the cerebellum (a central structure containing high levels of transgene expression and synthesis); the cerebella of wild type (C57Bl/6) and p75NTR-deficient mice lacked these sensory and sympathetic fibers. Both lines of transgenic animals also possessed a dense plexus of L1-immunoreactive axons in their cerebella; the spatial distribution of these L1-immunostained axons paralleled that seen for the sensory and sympathetic axons. A unilateral removal of the superior cervical ganglion in both lines of transgenic animals caused a complete reduction of tyrosine hydroxylase-immunopositive axons in the cerebellum but did not affect the density of L1-immunopositive axons. From these in vivo data, we conclude that collateral branches of sensory axons which invade a NGF-rich target area display L1 immunoreactivity, and that such immunodetection does not require the functional expression of p75NTR.
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PMID:p75-deficient sensory axons are immunoreactive for the glycoprotein L1 in mice overexpressing nerve growth factor. 966 23


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