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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nucleoside analog 2',3'-dideoxycytidine (ddC) is a potent inhibitor of the reverse transcriptase of human immunodeficiency virus and a DNA chain terminator. In clinical trials in patients with acquired immunodeficiency syndrome, ddC treatment has been associated with a dose-limiting and dose-dependent, painful, sensorimotor peripheral neuropathy. In search of an animal model for ddC-induced neurotoxicity we studied 36 New Zealand White rabbits (3 males/3 females/group) given 0, 10, 50, 100, 150, or 250 mg/kg/day of ddC, by oral intubation, for 13 or 18 weeks. Rabbits in the 150 and 250 mg/kg/day groups were sacrificed at 13 weeks because of hematopoietic toxicity. After 16 weeks, rabbits in the 50 and 100 mg/kg/day groups showed hindlimb paresis and/or gait abnormalities. Nerve conduction velocities and amplitudes in the 100 mg/kg/day rabbits were reduced by 30 to 50%. The most prominent pathologic changes in peripheral nerve and ventral roots of ddC-treated rabbits were (a) myelin splitting and intramyelinic edema, (b) demyelination and remyelination of axons, and (c) axonal loss. Treatment-related histologic lesions were not observed in spinal cord, brain, or retina. The pathology in these ddC-treated rabbits is consistent with a peripheral myelinopathy and axonopathy. This represents the first clinical, electrophysiologic, and pathologic description of an animal model of a peripheral neuropathy induced by a nucleoside analog.
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PMID:Peripheral neuropathy induced by 2',3'-dideoxycytidine. A rabbit model of 2',3'-dideoxycytidine neurotoxicity. 130 30

The development of the CNS is associated with an increasing use of the 30-bp variable alternative, spliced exon (VASE) in neural cell adhesion molecule (NCAM). We have assessed the relative usage of VASE by reverse transcriptase-linked polymerase chain reaction in the developing cerebellum and hippocampus at times when neurons isolated from these tissues can respond to substrate-associated NCAM by increased axonal growth and also at later developmental stages, when they are no longer responsive to substrate-associated NCAM. Neurons isolated from the developing cerebellum at postnatal day 6 respond to NCAM with increased neurite growth. NCAM transcripts from these cells were found to have negligible levels of VASE usage. In contrast, neurons that are isolated at later stages of development (postnatal days 8, 10, and 11) and do not respond to NCAM were found to synthesise a much higher proportion of NCAM transcripts containing VASE. In the hippocampus, embryonic day 18 neurons, which are responsive to NCAM, express low levels of VASE, whereas postnatal days 4 and 5 neurons, which are not responsive to NCAM, have a greater proportion of transcripts containing VASE. Thus, the level of NCAM VASE exon usage by neurons appears to be a good indicator of the ability of these cells to respond to non-VASE-containing NCAM (expressed in a cellular substratum) by increased neurite outgrowth.
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PMID:Use of the neural cell adhesion molecule VASE exon by neurons is associated with a specific down-regulation of neural cell adhesion molecule-dependent neurite outgrowth in the developing cerebellum and hippocampus. 140 33

Neurosteroids are steroids that are synthesized de novo in the brain and include some classical (adrenal and gonadal steroids) and some unique brain-specific steroids. Neurosteroids are thought to mediate their action through ion gated channel receptors such as gamma-aminobutyric acid(A) and N-methyl-D-aspartate rather than through classical nuclear steroid hormone receptors. Some enzymes involved in neurosteroidogenesis have been identified as those found in steroidogenic tissues, and some may be unique to the brain. We previously demonstrated that the messenger RNAs (mRNA) for the cholesterol side-chain cleavage enzyme, cytochrome P450scc, and one form of 11 beta-hydroxylase, cytochrome P450c11 beta, are regionally expressed in the adult rat brain. However, cytochrome P450c17, which has 17-hydroxylase and 17,20-lyase activity and is thought to be required for the synthesis of dehydroepiandrosterone, was not detected in any region of the rat brain, even though dehydroepiandrosterone is one of the most abundant neuroactive steroids. We now demonstrate that P450c17 is expressed in the nervous system of the developing rodent embryo. By ribonuclease protection assays, P450c17 mRNA was found in the trunk but not in the head of rat embryos but reverse transcriptase-polymerase chain reaction analysis showed expression of P450c17 mRNA in the head of E15.5 to E19.5 rat embryos. Immunocytochemically detectable P450c17 protein was expressed in the nervous system as early as embryonic day E10.5 in the mouse, mainly in tissue derived from the neural crest. Neuronal cell bodies as well as fibers staining for P450c17 were observed in the central and peripheral nervous systems. The sites of P450c17 expression in the peripheral nervous system suggest it may be involved in a wide variety of sensory-motor functions. In the central nervous system, cell bodies expressing P450c17 are found in the hind brain, in mesencephalic nuclei, and in a region in the location of the locus coeruleus, but in cells distinct from those expressing the dopamine-beta-hydroxylase. Furthermore, its particular location and temporal expression in axons reaching the cortical areas suggest it is a marker for the axonal growth in this region, and that its neurosteroid product may be a signal for targeting cortical axons during embryogenesis.
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PMID:Steroidogenic enzyme P450c17 is expressed in the embryonic central nervous system. 758 60

In the PNS, ciliary neurotrophic factor (CNTF) is found in significant amounts in the adult sciatic nerve, localized to myelin-related Schwann cells (SCs). Levels are undetectable in newborn but high in adult animals. After crush injury, CNTF production is reduced, recovering only as the nerve regenerates; if regeneration does not occur, CNTF levels remain low. We have examined the coupling of CNTF expression to myelination in vitro and in vivo to determine if axon-SC contact without myelination is sufficient to induce CNTF expression. Embryonic day 15 (E15) rat dorsal root ganglion (DRG) neuron and SCs were cocultured. CNTF was not detected in the DRGs either at E15 or after 2 days in vitro (div) by western blotting. However, after 10 div, CNTF could be identified and remained at constant levels up to 30 div. Depriving the cultures of ascorbic acid prevents myelination but not axon-SC contact. This did not affect CNTF protein production. Using reverse transcriptase-linked PCR (RT-PCR) techniques, no CNTF message was present in DRG from day 14 or 15 fetal rats; but by 6 days in culture, message was detected in both myelinating and nonmyelinating cultures. Isolated SC cultures, without axonal contact, failed to express CNTF protein; however, mRNA was detected by RT-PCR. Embryonic SC can be induced to synthesize CNTF in culture by axonal contact. Active myelination is not required.
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PMID:Ciliary neurotrophic factor expression in Schwann cells is induced by axonal contact. 761 10

Peripheral nerve crush induces novel projections from noradrenergic sympathetic neurons to sensory ganglia, and it has been suggested that these projections provide an anatomical substrate for chronic pain syndromes that occur after nerve injury. The present study demonstrates that novel sympathetic projections to sensory neurons are also induced in transgenic mice that overexpress nerve growth factor (NGF) in the skin. Specifically, a large proportion of trigeminal neurons in NGF transgenic mice were innervated by tyrosine hydroxylase (TH)-positive pericellular arborizations that were seen only rarely in controls. Electron microscopic analysis of NGF transgenic mice revealed that trigeminal neurons were surrounded by numerous axonal varicosities containing synaptic specializations. Removal of the superior cervical ganglion abolished TH-immunoreactive arborizations in the ipsilateral trigeminal ganglion confirming that these fibers were sympathetic axons. A two-site enzyme-linked immunosorbent assay revealed that transgenic ganglia contained a tenfold increase in NGF peptide compared to controls. However, reverse transcriptase polymerase chain reaction analysis showed no apparent expression of transgene mRNA in sensory ganglia, suggesting that the additional NGF was derived from increased NGF expression in the skin. These results indicate that NGF can induce novel sympathetic projections to sensory neurons in vivo and suggests a model in which increased NGF expression plays a role in the development of sympathetic hyperalgesia after nerve injury.
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PMID:Overexpression of nerve growth factor in transgenic mice induces novel sympathetic projections to primary sensory neurons. 785 36

Receptor tyrosine kinases (RTKs) play important roles in cellular proliferation, differentiation, and survival. We performed reverse transcriptase-polymerase chain reactions (RT-PCR) from enriched embryonic day 5 (E5) chick motoneurons by panning to identify RTKs involved in the early development of motoneuron. In situ hybridization revealed that Cek8, a member of the eph family, was specifically expressed on motoneurons at the brachial and lumbar segments of the spinal cord which innervate limb muscles, and disappeared after the naturally occurring cell death period (E6-E11). Immunohistochemistry using an anti-Cek8 monoclonal antibody showed the localization of Cek8 protein at the cell bodies and axonal fibers of motoneurons and muscles. The unique expression of Cek8 suggests its involvement in cellular survival or cell-cell interactions for specific subpopulations of developing motoneurons.
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PMID:The receptor tyrosine kinase, Cek8, is transiently expressed on subtypes of motoneurons in the spinal cord during development. 880 6

The myelin basic protein (MBP) gene locus is composed of two overlapping transcription units that share all of the MBP exons. One of these transcription units expresses the MBPs and the other expresses a family of proteins structurally related to the MBPs. This second transcription unit is called the Golli gene, and the entire complex is called the Golli-mbp gene. In this study, the expression of the Golli gene was examined in the human fetal central nervous system (CNS). By using reverse transcriptase-polymerase chain reaction cloning we have identified eight new members of the Golli gene family of transcripts expressed in the human CNS. Golli gene expression was examined by in situ hybridization and immunohistochemistry, and surprisingly, Golli products were found to be expressed in neurons as well as oligodendrocytes. Furthermore, the subcellular distribution of Golli immunoreactivity in fetal spinal cord interneurons shifted between the various laminae. Golli protein was localized within the nuclei of interneurons in the posterior horn, but was found in the cell bodies and processes of interneurons in the anterior horn. Within oligodendrocytes, Golli protein was detected in the cell bodies and processes, including processes which were wrapping axonal segments. Golli mRNA expression was also observed in neurons within the cerebral cortex between 18 and 20 weeks postconception, prior to myelination of this brain region. During this period, there was a striking developmental increase in the numbers and in the locations of neurons expressing Golli mRNAs within the cortical plate. The diverse distribution of Golli proteins within neurons and oligodendrocytes indicates that their function is quite different from that of the MBPs to which they are closely related.
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PMID:Expression of the myelin basic protein gene locus in neurons and oligodendrocytes in the human fetal central nervous system. 890 3

Cell surface proteoglycans (PGs) have been implicated in neuronal growth, migration and differentiation and can play pivotal roles both in cell-cell and cell-substrate interactions during the development of the nervous system. We have previously shown that glutamate activation of excitatory amino acid receptors induces the synthesis and release of PGs with neurite-promoting activity from hippocampal neurones. In this study, we have investigated the activity-dependent regulation of mRNA expression of two PGs in fetal hippocampal neurones using a competitive reverse transcriptase-polymerase chain reaction and correlated this expression with neuronal growth. Both cerebroglycan (CBG), a glycosylphatidylinositol-anchored heparan sulphate PG, and neurocan, a developmentally regulated chondroitin sulphate PG, are expressed in hippocampal neurones. Exposure of hippocampal neurones to 100 microM glutamate for 5 min resulted in an increase in CBG mRNA levels and an increase in axonal and dendritic length. The increase in CBG mRNA levels following glutamate exposure was mediated via both N-methyl-D-aspartate and metabotropic receptor activation.
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PMID:Differential regulation of neuronal proteoglycans by activation of excitatory amino acid receptors. 910 42

Neurotrophins are known to influence Schwann cells during development and to promote peripheral nerve regeneration after axonal damage. In neoplastic conditions. Schwann cells from experimentally-induced schwannomas appear to retain their responsiveness to nerve growth factor (NGF), although the role of neurotrophins in the neoplastic process in poorly understood. In this study, human neoplastic Schwann cells (five cases of acoustic schwannoma and two cases of malignant peripheral nerve sheath tumours [MPNST]) were investigated for the expression in situ of molecules of the neurotrophin system. In particular, we studied the 75 kDa low-affinity receptor (p75) and the mRNA for its ligands, NGF and neurotrophin-3 (NT-3). By immunohistochemistry, the p75 receptor was found to be the present at high levels in Schwann cells from acoustic schwannomas, whereas it was very weak or absent in MPNST. Messenger RNA for NGF and NT-3 was detected by reverse transcriptase in situ polymerase chain reaction technique and showed the same fluctuation of p75, being up-regulated in acoustic schwannomas and very weak or absent in MPNST. In normal non-neoplastic tissue, no detectable amounts of either ligand or receptor were observed. Our results indicate that changes in the expression of neurotrophins and their p75 receptor occurred during the neoplastic transformation of Schwann cells. In benign schwannomas, such changes are likely to reflect the loss of axonal contact, while in MPNST they may be related to a complete derangement of cell machinery in the tumour cells.
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PMID:Human neoplastic Schwann cells: changes in the expression of neurotrophins and their low-affinity receptor p75. 936 63

Brainstem serotonin (5-HT)-containing cells are remarkable for their widespread axonal projections and having their highest activity during wakefulness and lowest during rapid eye movement sleep. One important site of action of 5-HT is on upper airway motoneurons. However, which of the 14 known 5-HT receptors mediate the effects is uncertain. We used the reverse transcriptase/polymerase chain reaction to detect mRNA for six distinct 5-HT receptors (1A, 1B, 2A, 2C, 3 and 7) in 50 nl micro-punches collected from the hypoglossal (XII) motor nucleus and, for comparison, from the viscerosensory nucleus of the solitary tract (NTS) in adult rats. The relative abundance of the distinct mRNAs was characterized by the minimal number of amplification cycles (25-40) necessary to detect a given mRNA. In the XII nucleus, mRNA for type 1B, 2A and 2C receptors was detectable after 29-31 cycles, detection of type 3 and 7 receptor mRNA required 33-35 cycles; and type 1A receptor mRNA was not detected. In the NTS, detection of mRNA for type 1B, 2C and 7 receptors required 31-33 cycles; type 1A receptor mRNA required 39 cycles; and type 2A receptor mRNA was not detected. The data from the XII nucleus demonstrate that not only the previously recognized type 1B, 2A and 2C receptors, but also type 3 and 7 receptors have the potential to mediate serotonergic effects in XII motoneurons.
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PMID:Serotonin receptor mRNA expression in the hypoglossal motor nucleus. 940 8


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