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)

Using in situ hybridization, we examined the distribution of the mRNA encoding for the growth-associated protein GAP-43 in the brain stem of adult rats. GAP-43 was expressed at the highest level in the nucleus raphe dorsalis (NDR), nucleus centralis superior (NCS), substantia nigra compacta (SNc), ventral tegmental area (VTA), and locus coeruleus (LC). An intermediate level of signal was detected over the periaque-ductal gray, superior colliculi, and thalamic region, and no significant signal was detected in the substantia nigra pars reticulata and red nucleus. The hybridization signals of GAP-43 mRNA and tryptophan hydroxylase mRNA completely overlapped in the NDR and NCS, and signals for GAP-43 mRNA and tyrosine hydroxylase mRNA overlapped in the SNc, VTA, and LC. The disappearance of the hybridization signal for GAP-43 mRNA after intracerebroventricular injections of the neurotoxins 5,7-dihydroxytryptamine (5,7-DHT) or 6-hydroxydopamine (6-OHDA) indicated that high levels of GAP-43 are synthesized in the serotonergic neurons of the raphe nuclei and in the catecholaminergic neurons of the SNc, VTA, and LC. In light of the role of GAP-43 in axonal outgrowth, modulation of signal transduction, and release of different neurotransmitters in the adult CNS, this phosphoprotein might be involved in the functional plasticity and synaptic transmission of monoaminergic neurons.
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PMID:Distribution of GAP-43 mRNA in the brain stem of adult rats as evidenced by in situ hybridization: localization within monoaminergic neurons. 167 51

The persistence of high levels of B-50 (GAP-43) in fibers innervating various regions of the adult central nervous system is generally thought to characterize neuronal systems capable of undergoing morphological plasticity. In a recent series of in situ hybridization studies, it has been shown that most catecholaminergic and serotonergic neurons of the adult rat brain express high levels of B-50 mRNA. The present study addresses the question whether high expression of B-50 mRNA in the catecholaminergic and serotonergic perikarya corresponds with detectable high levels of the B-50 protein in the efferent axonal fibers that innervate various regions of the adult rat brain and spinal cord. For this purpose, vibratome sections were doubly immunostained for B-50 and for tyrosine hydroxylase or serotonin and were analyzed by laser scanning confocal microscope. Colocalizations were investigated either (1) in regions of intact rat brain and spinal cord in which particular concentrations of B-50 immunoreactive fibers appeared codistributed with catecholaminergic or serotonergic fibers or (2) in intrahypothalamic portions of the medial forebrain bundle in which a surgical lesion was made. In the intact brain, frequent colocalizations of B-50 and tyrosine hydroxylase were detected in fibers innervating both the mediobasal hypothalamus and the neurointermediate hypophysial lobe. In all the other regions examined, the analysis of thin optical sections demonstrated that immunoreactivity to B-50 was only rarely associated with axonal profiles immunoreactive to tyrosine hydroxylase or to serotonin. By contrast, in the lesioned medial forebrain bundle B-50 immunoreactivity was found to be associated with numerous catecholaminergic and serotonergic axonal sprouts that regenerate around the surgical lesion. These data indicate that the majority of intact catecholaminergic and serotonergic axons innervating the adult rat brain and spinal cord contains low levels of B-50. However, following axotomy, B-50 is immunocytochemically detectable in the regenerating sprouts produced by both types of axonal fibers. This suggests that under basal conditions the relatively high content of B-50 mRNA in monoaminergic perikarya does not lead to appreciable accumulation of B-50 within corresponding axonal fibers and terminals, whereas conditions of morphological reorganization induce increased production of B-50 that accumulates within monoaminergic axonal sprouts.
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PMID:B-50 (GAP-43) immunoreactivity is rarely detected within intact catecholaminergic and serotonergic axons innervating the brain and spinal cord of the adult rat, but is associated with these axons following lesion. 754 87

In this study we use dissociated cell cultures of the rat carotid body to investigate the adaptive capabilities of endogenous oxygen chemoreceptors, following chronic stimulation by various environmental factors. These oxygen chemoreceptors are catecholamine-containing glomus cells, which derive from the neural crest and resemble adrenal medullary chromaffin cells. Using double-label immunofluorescence, we found that chronic exposure of carotid body cultures to hypoxia (2% to 10% oxygen) caused a significant fraction of tyrosine hydroxylase-positive (TH+) glomus cells to acquire detectable immunoreactivity for growth-associated protein GAP-43. The effect was dose-dependent and peaked around an oxygen tension of 6%, where approximately 30% of glomus cells were GAP-43 positive. Treatment with agents that elevate intracellular cyclic adenosine monophosphate (cAMP) (i.e., dibutyryl cAMP or forskolin) also markedly stimulated GAP-43 expression. Since hypoxia is known to increase cAMP levels in glomus cells, it is possible that the effect of hypoxia on GAP-43 expression was mediated, at least in part, by a cAMP-dependent pathway. Unlike hypoxia, however, cAMP analogs also stimulated neurofilament (NF 68 or NF 160 kD) expression and neurite outgrowth in glomus cells, and these properties were enhanced by retinoic acid. Nerve growth factor, which promotes neuronal differentiation in related crest-derived endocrine cells, and dibutyryl cGMP were ineffective. Thus, it appears that postnatal glomus cells are plastic and can express neuronal traits in vitro. However, since hypoxia stimulated GAP-43 expression, without promoting neurite outgrowth, it appears that the two processes can be uncoupled. We suggest that stimulation of GAP-43 by hypoxia may be important for other physiological processes, e.g., enhancing neurotransmitter release or sensitization of G-protein-coupled receptor transduction.
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PMID:Plasticity in cultured carotid body chemoreceptors: environmental modulation of GAP-43 and neurofilament. 760 13

Expression of mRNAs encoding the dopamine transporter (DAT) and tyrosine hydroxylase (TH) in dopaminergic neurons of the substantia nigra (SN) was examined in young and aged Fischer 344 rats by in situ hybridization. Quantitative analysis revealed a statistically significant decline in both DAT and TH mRNA expression in 24-month-old rats in comparison to 6-month-old rats. In addition, it was noted that DAT mRNA expression tended to decrease by 18 months, while TH mRNA reduction did not occur until 24 months. The age-related loss of DAT and TH mRNA expressions was accompanied by diminished expression of mRNA for a neuronal growth-associated protein GAP-43, but not for SCG10 or alpha 1-tubulin. The loss of GAP-43 mRNA became evident when both DAT and TH gene expression declined with advanced age. Our findings indicate that DAT may be a marker of atrophy in dopamine neurons during normal aging.
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PMID:Reduced expression of the molecular markers of dopaminergic neuronal atrophy in the aging rat brain. 761 30

The presence of the growth-associated protein, GAP-43, in rat sciatic nerve and gastrocnemius muscle was studied, using indirect immunofluorescence, in lumbar sympathectomized and sham-sympathectomized rats. To study fast axonal transport and accumulation of immunogenic GAP-43, the sciatic nerves were crush operated, 6 h before perfusion fixation. In sections of normal, crushed sciatic nerve GAP-43-like immunoreactivity (LI) rapidly accumulated, on both sides of the crushes, in medium and thin sized axons. In double immunostaining experiments, GAP-43-LI was mainly colocalized with tyrosine hydroxylase (TH)-LI, or neuropeptide Y (NPY)-LI, markers of sympathetic nerves. In some axons, GAP-43-LI was colocalized with Substance P (SP)-LI. In perivascular nerve terminals in the gastrocnemic muscle, strong GAP-43-immunofluorescence was observed, in most cases colocalized with TH-LI, but in some terminals with SP-LI. Three days after lumbar sympathectomy (removal of the L1-L4 sympathetic ganglia bilaterally), TH-LI and NPY-LI positive axons in the sciatic nerve were reduced in number by more than 90%. GAP-43-LI positive axons were reduced by about 50%. In the gastrocnemic muscle, some GAP-43-LI positive terminals, but very few TH-LI positive nerve fibres, were found around blood vessels. No further changes were seen 8 days after sympathectomy. SP-LI in axons in the sciatic nerve and in perivascular nerve terminals of the gastrocnemic muscle, did not change after sympathectomy; most of these axons also contained GAP-43-LI. S-100-LI was present periaxonally in the sciatic nerves, but it did not colocalize with GAP-43, indicating that Schwann cells contained no GAP-43-LI in these experiments. The results show that, in normal adult rats, GAP-43-LI is mainly present in sympathetic and sensory nerve fibers in sciatic nerve and in perivascular nerve terminals. The peptide is axonally transported, mainly in sensory and adrenergic axons.
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PMID:GAP-43 and its relation to autonomic and sensory neurons in sciatic nerve and gastrocnemius muscle in the rat. 771 24

Mesencephalic cell suspensions were prepared from E12 wild-type (+/+) mouse embryos and stereotaxically implanted into the dorsal neostriatum of weaver mutant mice (wv/wv), which have a genetic mesostriatal dopamine (DA) deficiency. Survival of DA neurons in the grafts was documented by tyrosine hydroxylase (TH) immunocytochemistry. Axon growth was monitored by immunocytochemistry using a battery of antibody markers, and the cellular localization of structural protein and receptor RNA transcripts was studied by in situ hybridization histochemistry using [32P]oligonucleotide probes. The cell suspension grafts exhibited strong immunoreactivity for neural cell adhesion molecule (N-CAM), growth-associated phosphoprotein GAP-43, microtubule-associated protein 2 (MAP2), beta-amyloid protein precursor (beta APP), and phosphorylated neurofilament epitopes (clone SMI-31); intermediate-to-high levels of immunoreactivity were seen for synaptophysin. High levels of hybridization were found in the grafts for the RNA transcripts of GAP-43, MAP2, and isoforms beta APP695, beta APP714 and beta APP751 of the beta APP. No hybridization signal was detected in the grafts for DA D2 or neurotensin receptor mRNAs, both of which are normally expressed by nigral DA neurons. DA receptor autoradiography using the D2/D3 agonist [3H]CV 205-502 as a ligand showed no binding in the transplants, indicating an apparent abnormality of grafted cells; neurotensin binding sites, labeled with [125I]neurotensin, were visualized in the suspensions, indicating the possibility that receptors could be present but that RNA message levels might be too low to allow detection. These findings offer a molecular correlate of axonal, dendritic and structural protein expression by transplanted mesencephalic neurons; further, they suggest that specific functional properties of grafted nigral cells are maintained after transplantation, while other aspects of their cellular biology may be compromised.
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PMID:Ventral mesencephalic grafts in the neostriatum of the weaver mutant mouse: structural molecule and receptor studies. 772 32

Fibers labelled with antibody to the growth associated protein (GAP-43) were observed as early as 4 gestational weeks (g.w.) in the nervous system of human embryos. At 6 g.w. these fibers could be traced throughout the brainstem and the diencephalon. None of the immunolabeled fibers entered the telencephalic wall at that point, but 2 weeks later at 8 g.w., GAP-43 positive fibers were observed below the newly formed cortical plate of the cerebral cortex. GAP-43 positive fiber bundles had the same distribution as those previously labeled with tyrosine hydroxylase antibodies at the same age. These results strongly suggest that this growth associated protein is localized in the early growing dopaminergic fibers.
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PMID:Immunocytochemical localization of growth-associated protein GAP-43 in early human development. 774 48

The 'growth-associated protein', GAP-43 was originally considered to be a neuron-specific protein associated with plasticity. However, we have recently shown that GAP-43 is expressed by noradrenergic, but not by adrenergic chromaffin cells in the adult rat adrenal gland. In this study, we examine the expression of GAP-43 during embryonic and post-natal development of the adrenal gland using immunohistochemical techniques. In parallel, antibodies directed against two neuroendocrine markers, the catecholamine-synthesizing enzymes, tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) were employed to permit identification of the developing chromaffin cell phenotypes. At embryonic day 15.5, GAP-43 was predominately localized in sympathoadrenergic precursor cells in the extra-adrenal blastema, and also in nerve fibers within the adrenal gland. At later embryonic stages, GAP-43 was expressed by nearly all intra-adrenal chromoblasts. Two subsets of chromoblasts can be distinguished even at early stages. A strong GAP-43-positive immunoreaction was observed in those chromoblasts organized in a few large compact clusters which weakly expressed TH and did not express PNMT. A generally weaker GAP-43 immunoreaction was observed in a second type of intra-adrenal chromoblasts which were organized in small isolated groups and characterized by a PNMT-positive, and strong TH-positive immunoreactivity. GAP-43 immunoreactivity was still associated with many PNMT-positive adrenergic chromoblasts at birth, but decreased to undetectable levels during the first post-natal week. By the second post-natal week, GAP-43 was restricted, as in the adult, to noradrenergic chromaffin cells which expressed TH, but not PNMT, in addition to nerve fibers and their associated glial cells in the gland. An immunoblot analysis confirmed a decrease in GAP-43 protein during the post-natal period. In agreement with these observations, a three-fold decrease in GAP-43 mRNA in the adrenal gland was measured between late embryogenesis and the second post-natal week. During development, the spatiotemporal expression of GAP-43 suggests a possible role in the migration and aggregation of chromaffin cell precursors into the medullary region of the adrenal gland.
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PMID:Expression of GAP-43 (neuromodulin) during the development of the rat adrenal gland. 784 14

We have localized at light and electron-microscopic level the growth-associated protein GAP-43 in adrenal gland using single and double labelling immunocytochemistry. Clusters of GAP-43-immunofluorescent chromaffin cells and many immunofluorescent fibres were observed in the medulla. GAP-43-immunoreactive fibres also formed a plexus under the capsule, crossed the cortex and ramified in the zona reticulata. Double labelled sections showed the coexpression of GAP-43 with a subpopulation of tyrosine hydroxylase- and of dopamine-beta-hydroxylase-immunoreactive chromaffin cells. Dual colour immunofluorescence for GAP-43 and calcitonin gene-related peptide (CGRP) revealed that some of the GAP-43-immunoreactive fibres also express CGRP. Pre-embedding electron microscopy showed GAP-43 immunoreactivity associated with the plasma membranes and cytoplasm of noradrenaline-producing chromaffin cells, and with processes of nonmyelin-forming Schwann cells. Immunoreactive unmyelinated axons and terminals were also observed. The immunostained terminals made symmetrical synaptic contacts with chromaffin cells. Immunoreactive unmyelinated fibres and small terminals were present in the cortex. Our results show that GAP-43 is expressed in noradrenergic chromaffin cells and in various types of nerve fibres that innervate the adrenal. Likely origins for these fibres include preganglionic sympathetic fibres which innervate chromaffin cells, postganglionic sympathetic fibres in the cortex, and CGRP containing sensory fibres.
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PMID:Immunocytochemical localization of a growth-associated protein (GAP-43) in rat adrenal gland. 790 51

A CNS catecholaminergic cell line, Cath.a, was established by targeted oncogenesis in transgenic mice. Cath.a cells express neuronal properties but lack neuronal morphology. Here, we describe a variant of Cath.a, called CAD (Cath.a-differentiated), in which reversible morphological differentiation can be initiated by removal of serum or exogenously added protein from the medium. In serum- or protein-free media, CAD cells stop proliferating and extend long processes. Differentiated CAD cells can be maintained without serum or protein for at least 6 weeks. CAD cells are distinct from Cath.a cells; most significant, the original immortalizing oncogene, SV40 T antigen, was spontaneously lost. By immunostaining or immunoblotting, we show that CAD cells express neuron-specific proteins, such as class III beta-tubulin, GAP-43, SNAP-25, and synaptotagmin, but not GFAP. Ultrastructurally, processes from differentiated CAD cells have abundant parallel microtubules and intermediate filaments, and bear varicosities that contain both large dense-core vesicles/granules (120-160 nm) and smaller clear vesicles (60-80 nm). Additionally, CAD cells express enzymatically active tyrosine hydroxylase and accumulate L-DOPA. CAD cells exhibit biochemical and morphological characteristics of primary neurons and provide an unique tool for studying neuronal differentiation.
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PMID:Characterization of a CNS cell line, CAD, in which morphological differentiation is initiated by serum deprivation. 900 67


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