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At least 19 recordsLinked to original sources
PubMed1992

Differential expression of growth-associated protein (GAP-43) mRNA in rat primary sensory neurons after peripheral nerve lesion: a non-radioactive in situ hybridisation study.

An alkaline phosphatase-labelled anti-sense oligodeoxynucleotide probe specific for growth-associated protein messenger RNA (GAP-43 mRNA) was used for non-radioactive in situ hybridisation histochemistry to follow relative changes in GAP-43 mRNA content in lumbar primary sensory neurons (L4-6) after unilateral ligation of the sciatic nerve. In normal dorsal root ganglia (DRG) 16% of neurons expressed GAP-43 mRNA, and these cells belonged to a sub-group of intermediate-sized (32-50 microns diameter) and large (> 50 microns) neurons. The hybridisation signal detected in these cells was weak to moderate. One day after nerve ligature a significant increase in the number of GAP-43 mRNA expressing neurons in the ipsilateral DRG was detected involving particularly the very small (12-20 microns) cells, and small cell population (20-32 microns), though the hybridisation signal was less pronounced in this latter cell group. A significant increase in the cellular content of GAP-43 mRNA was detected in both cell groups when compared to the normal DRG by 2 days after the lesion. At later times (4, 7, and 10 days postinjury) the intermediate-sized and large cell subpopulations also showed an increase in the number of GAP-43 mRNA positive neurons, followed by a significant rise in their content of GAP-43 mRNA. However, they did not reach the same intensity of hybridisation signal as seen in the small and very small neurons. All DRG neurons showed a maximum of GAP-43 mRNA expression by 10 days postsurgery. At longer times there was a slight decrease in the content of GAP-43 mRNA towards 14 days postinjury, but mRNA levels remained elevated up to 28 days after nerve ligature, the longest time point examined in this study. The different onset and levels of GAP-43 gene expression in the rat primary sensory neurons after lesion of their peripheral branch axons further characterize the different subclasses of these cells and may reflect their different involvement in the plastic changes following peripheral nerve injury.

Alkaline Phosphatase↗
PubMed1992

Protein kinase C subspecies in rat brain synapses and phosphorylation of growth-associated protein.

Synaptosomes isolated from rat hippocampus contained the alpha- and beta-subspecies of protein kinase C (PKC), but not the gamma-subspecies, whereas postsynaptic pyramidal cells contained all these three subspecies. The PKC enzymes were activated synergistically by diacylglycerol and cis-unsaturated fatty acids including docosahexaenoic acid which is abundant in brain phospholipids. The phosphorylation of a PKC-specific substrate, growth-associated protein (GAP-43), which is associated predominantly with presynaptic membranes, was also protein (GAP-43), which is associated predominantly with presynaptic membranes, was also stimulated by diacylglycerol and cis-unsaturated fatty acids, particularly at the micromolar range of Ca2+ concentrations. The results presented suggest that cis-unsaturated fatty acids together with diacyglycerol may take part in the phosphorylation of GAP-43 in presynaptic membranes presumably by the alpha- or beta-subspecies of PKC even after the Ca2+ concentrations return to the basal level.

Animals↗
PubMed1992

GAP-43 mRNA localization in the rat hippocampus CA3 field.

Gene expression of the axonal growth-associated protein, GAP-43, has been studied in the adult rat brain by in situ hybridization histochemistry. This protein is synthesized at high levels in neuronal somata in immature and regenerating neurons, but after establishment of mature synaptic relations its synthesis generally declines sharply, thus providing a marker denoting propensity for exhibiting synaptic plasticity. Detailed examination of the distribution of mRNA for GAP-43 in rat hippocampus is selectively and robustly expressed in the pyramidal neurons of field CA3 and, to a lesser extent, the polymorph neurons of the hilus of the dentate gyrus. Additional hippocampal regions of moderate expression include the tenia tecta and the subicular and entorhinal fields, but CA1 and CA2 are strikingly lower in signal. The significance of this pattern of localization is considered in the context of the phosphorylation of GAP-43 and its role in influencing synaptic events underlying the establishment and maintenance of long-term potentiation and plasticity in the hippocampus.

Animals↗
PubMedDate not supplied

Reduced GAP-43 message levels are associated with increased neurofibrillary tangle density in the frontal association cortex (area 9) in Alzheimer's disease.

We previously suggested the hypothesis that defective neuronal plasticity is a major neurobiological deficit causing the dementia of Alzheimer's disease (AD). We used message levels of the growth-associated protein, GAP-43, as a marker of axonal plasticity to examine the hypothesis of defective neuronal plasticity in AD. When all AD cases are combined, the average level of GAP-43 message in area 9 of the AD frontal association cortex was not significantly different from the level in the comparably aged control cortex. Differentiation of AD cases on the basis of neurofibrillary tangle (NFT) density revealed that in AD cases with high tangle density average GAP-43 message level was reduced fivefold relative to levels in AD cases with low NFT density. AD cases with low neurofibrillary tangle density had levels of GAP-43 message that were not significantly different from the levels of normal controls. Differentiation of AD cases on the basis of neuritic plaque density did not indicate as strong a relationship to GAP-43 message level. The association between neurofibrillary tangle density and GAP-43 message level suggests the hypothesis that neurofibrillary tangles may reduce GAP-43 expression. Data of others show a relationship between high NFT density and reduced levels of synaptophysin-like immunoreactivity and reduced cerebral glucose metabolism. These data combine to suggest a set of AD cases with high NFT density, reduced axonal plasticity, reduced synaptic density, and reduced cerebral glucose metabolism--all variables that may be directly related to the functioning of the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Calcitonin gene-related peptide, substance P and GAP-43/B-50 immunoreactivity in the normal and arthrotic knee joint of the mouse.

The aim of this study was to describe the normal distribution of calcitonin gene-related peptide (CGRP) and substance P (SP) containing fibres in the knee joint of the mouse and to obtain insight into the changes in innervation associated with degenerative processes in the joint. Arthrosis was induced by a single subpatellar intra-articular injection of bacterial collagenase. After decalcification in EDTA solutions, the CGRP and SP fibres were visualized by peroxidase-antiperoxidase pre-embedding immunocytochemistry for light microscopy. Control experiments on the mouse brain as a reference for the effect of EDTA on the immunostaining showed that the decalcification procedure with EDTA had not impaired the immunostaining. A rich innervation of thin varicose CGRP and SP immunoreactive fibres was found in most peri- and intra-articular tissue components. The periosteum, synovial tissues, the joint capsule and the intra-articular fat tissues were richly innervated. Less intense innervations were also found in the subchondral bone plates of the tibio-femoral joint and of the patella. Fibres were also found in the soft tissues between the patellar tendon and the femoral groove. No differences could be found between the location of CGRP and SP fibres with respect to the localization in the joint, but generally more CGRP fibres were found. The collagenase-induced osteoarthrosis was characterized by sclerosis of the subchondral bone, patellar dislocation, osteophyte formation, synovial proliferation and by severe cartilage abrasion, particularly on the medial side of the femoro-tibial joint. The overall distribution of CGRP and SP fibres was the same as in the control joints. However, major differences were found in all studied joints at specific locations around the cruciate ligaments, in the synovium around the patella, in the soft tissues lateral of the patella and in plica tissue between the patella and femoral groove. The CGRP and SP innervation was no longer detectable by immunolabelling with the antibodies. With a polyclonal antibody to the growth associated protein GAP-43/B-50, signs of degenerated axonal profiles were observed in these locations. At other peripheral locations, such as the muscles, the GAP-43/B-50 distribution was normal. In conclusion, the present study provides detailed information on the localization of CGRP and SP fibres, which may be involved in pain perception. Knowledge of the changes that occur during arthrosis may give more insight into the clinical symptoms.

Animals↗
PubMed1992

GAP-43 in non-neuronal cells of the embryonic chick limb: clues to function.

The expression of GAP-43 in developing and regenerating neurons has been well characterized, but the function of this membrane-bound phosphoprotein is still unclear. Although GAP-43 is considered to be neuron-specific, it is also expressed in various glial cells of the peripheral and central nervous systems and in at least two populations of mesenchymal cells in the developing chick limb. GAP-43 mRNA is expressed transiently in developing limbs, which contain axons of spinal cord and dorsal root ganglion neurons, but do not contain neuronal cell bodies. This expression is correlated temporally with the in-growth of neurites and axons to the limbs, but appears to be independent of nerves. In some regions of the limb, GAP-43 immunoreactivity co-localizes in cells that are also immunoreactive for meromyosin, a muscle-specific marker. In addition, GAP-43 mRNA and protein are particularly abundant in the interdigital mesenchyme that undergoes apoptosis, or programmed cell death. GAP-43 has been postulated to mediate rapid changes in cell shape and the extension of processes in neuronal growth cones and elongating axons. We suggest here that GAP-43 may serve a similar function in glial cells, in myoblasts fusing to form myotubes, and in apoptotic and phagocytic cells of the interdigital mesenchyme.

Animals↗
PubMed1992

Protein phosphatases 1 and 2A dephosphorylate B-50 in presynaptic plasma membranes from rat brain.

The protein B-50 is dephosphorylated in rat cortical synaptic plasma membranes (SPM) by protein phosphatase type 1 and 2A (PP-1 and PP-2A)-like activities. The present studies further demonstrate that B-50 is dephosphorylated not only by a spontaneously active PP-1-like enzyme, but also by a latent form after pretreatment of SPM with 0.2 mM cobalt/20 micrograms of trypsin/ml. The activity revealed by cobalt/trypsin was inhibited by inhibitor-2 and by high concentrations (microM) of okadaic acid, identifying it as a latent form of PP-1. In the presence of inhibitor-2 to block PP-1, histone H1 (16-64 micrograms/ml) and spermine (2 mM) increased B-50 dephosphorylation. This sensitivity to polycations and the reversal of their effects on B-50 dephosphorylation by 2 nM okadaic acid are indicative of PP-2A-like activity. PP-1- and PP-2A-like activities from SPM were further displayed by using exogenous phosphorylase alpha and histone H1 as substrates. Both PP-1 and PP-2A in rat SPM were immunologically identified with monospecific antibodies against the C-termini of catalytic subunits of rabbit skeletal muscle PP-1 and PP-2A. Okadaic acid-induced alteration of B-50 phosphorylation, consistent with inhibition of protein phosphatase activity, was demonstrated in rat cortical synaptosomes after immunoprecipitation with affinity-purified anti-B-50 immunoglobulin G. These results provide further evidence that SPM-bound PP-1 and PP-2A-like enzymes that share considerable similarities with their cytosolic counterparts may act as physiologically important phosphatases for B-50.

Animals↗
PubMed1992

Expression of growth-associated protein 43 and nerve growth factor receptor in human skin: a comparative immunohistochemical investigation.

The growth-associated protein 43 (GAP43) is a neuronal membrane protein involved in axonal growth and regeneration as well as in the modulation of synaptic plasticity. It is present in sensory and sympathetic neurons, where it is consistently associated with the expression of nerve growth factor receptor (NGFr). We investigated, by means of immunohistochemistry, the presence and distribution of the GAP43-immunoreactivity (IR) and of the NGFr-IR in the adult normal human skin from various body regions. In adjacent sections, a comparison with the distribution of the neuronal markers protein gene product 9.5 (PGP 9.5), substance P (SP), and calcitonin gene-related peptide (CGRP) was performed. Our results indicate that in adult human skin 1) a GAP43-IR is morphologically present in epidermal and dermal nerve fibers; 2) a NGFr-IR is associated with neuronal as well as non-neuronal elements of cutaneous nerves; 3) the basal epidermal cell layer expresses a NGFr-IR, which is unevenly distributed according to the different body areas; and 4) there is suggestive evidence for a simultaneous expression of GAP43-, NGFr-, PGP 9.5-, SP-, and CGRP-IR in at least part of the cutaneous nerve fibers. The presence of GAP43-immunoreactive nerve fibers might be a marker of a continuous synaptic remodeling in adult skin, whereas the distribution of the NGFr-IR could be relevant for our understanding of the maintenance of the neuronal-target relationship(s).

Adult↗
PubMed1992

Redistribution of B-50/growth-associated protein 43 during differentiation and maturation of rat hippocampal neurons in vitro.

Morphologically polarized hippocampal neurons, grown in culture for two days, contain immunoreactivity of the growth-associated protein B-50 along the plasma membrane of both dendrites and axons. In mature hippocampal neurons, both in vitro and in vivo, B-50 is located in the axon. In order to assess at which stage during neuronal differentiation B-50 is selectively located in the axon, an immuno-light and electron-microscopic study was performed on rat hippocampal neurons developing in vitro. B-50 immunofluorescence was detected in the axon, dendrites and soma of two-day-old polarized neurons. Simultaneously, microtubule-associated protein 2, a marker specific to dendritic microtubules, was predominantly found in the soma, the short dendritic processes and at the base of axonal growth cones. In hippocampal neurons cultured beyond seven days in vitro, microtubule-associated protein 2 immunofluorescence is restricted to the cell soma and dendrites. The spatial distribution of B-50, however, varies. In solitary neurons maturing without interneuronal contacts, B-50 immunofluorescence is observed in axons and in the dendrosomatic domain characterized by the presence of microtubule-associated protein 2. In contrast, in high-density cell cultures B-50 immunofluorescence is absent in the cell body and dendrites, but punctate in axons running along the dendrites. Electron microscopy was carried out on hippocampal neurons of eight to 21 days in vitro to study the process of redistribution of B-50 at the subcellular level. In neurons of eight days in vitro with prominent synapses, B-50 immunoreactivity is significantly elevated at the axonal plasma membrane compared to the plasma membrane of the dendrites and the soma. In neurons from the same culture without synapses, B-50 immunoreactivity is distributed rather densely along the plasma membrane of the soma, dendrites, and on the axonal plasma membrane. A similar B-50 distribution is observed in mature neurons cultured at low cell density without interneuronal cell contacts, for 15 days in vitro. In high-density cell cultures of 21 days in vitro, B-50 is virtually absent at the plasma membrane of the soma and dendrites, and heterogenously distributed along the plasma membrane of axon and axonal varicosities. Our results indicate that selective sorting of B-50 into axons occurs after initial morphological polarization of hippocampal neurons and is correlated with the formation of synapses and with the cessation of dendritic outgrowth.

Animals↗
PubMedDate not supplied

Stimulation by melanocortins of neurite outgrowth from spinal and sensory neurons in vitro.

Using ELISAs for B-50/GAP43 and neurofilament (NF), we tested ACTH(1-24), alpha-MSH, ACTH(4-10), and an ACTH(4-9) analogue (ORG2766) for their ability to induce sprouting and neuritogenesis from spinal and sensory neurons. Dissociated fetal rat spinal cord neurons or neonatal rat dorsal root ganglion (DRG) cells were cultured with peptide and assayed after 24, 48, or 96 h. In spinal neurons, alpha-MSH and ACTH(1-24) induced the expression of B-50 dose dependently. After 24 h alpha-MSH had a stimulatory effect (from 10 nM onwards), with a maximum at 100 microM (36% increase). After 96 h the maximal effect of 100 microM alpha-MSH on B-50/GAP43 was lower (19%). ACTH(1-24) (100 microM) stimulated B-50/GAP43 by 19%. Neurofilament levels (96 h) were elevated maximally by 64% at 100 microM alpha-MSH. In DRG neurons a bell-shaped dose-response curve was found for alpha-MSH, the maximal effect being observed after 48 h at 100 nM: 54% for B-50/GAP43 and 22% for NF. In both culture systems neither ACTH(4-10) nor ORG2766 was effective. We conclude that alpha-MSH stimulates the expression of B-50/GAP43 (sprouting) and the formation of NF (neurite elongation) and may therefore be considered a neurotrophic factor.

Adrenocorticotropic Hormone↗
PubMed1992

[Problem of chemical structural specificity of the brain].

The structurally specific chemical factors (SSCF) are considered as are differentiation-, regeneration- and normal function-promoting factors of embryonic and adult brain tissue. From this point of view the authors' data concerning SSCF expression after brain lesion are discussed. Analysis is made of the importance of further studies into the identification of these factors and elucidation of the biological role they play in the compensatory processes after brain damage in order to develop new approaches to the treatment of brain diseases.

Brain↗
PubMed1992

Multiple elements may be used for regulation of the GAP-43 gene in different cell-types.

Recent evidence suggests that GAP-43 expression is not restricted to the nervous system, but may also occur outside the neural cell lineage. Two distinct patterns of GAP-43 regulation can therefore be distinguished. The first is the regulation of GAP-43 expression in multiple cell-types, and the second is the gene's temporal modulation within one specific cell-type. The latter type is well documented for neurons, where GAP-43 regulation is regulated in a fashion that is dependent on axon integrity. Results from partial analysis of the GAP-43 promoter/enhancer region indicate that at least some of these aspects of GAP-43 gene regulation may be accounted for by distinct cis-acting elements. For example, the expression of a rat GAP-43 promoter fusion gene in epidermal cells of transgenic zebrafish is dependent on an enhancer element, that is clearly distinct from the minimal neural-specific promoter. Characterization of specific GAP-43 regulatory elements responsible for particular aspects of its regulation may provide insight to signal pathways also utilized by other genes during development. Ultimately, a better understanding of the molecular events during development could help to define more precisely the complex sequences necessary for the establishment of an intact organism.

Animals↗
PubMed1992

Functional domains of neuromodulin (GAP-43).

Although neuromodulin (GAP-43, B50, F1, pp46, protein 4) was first identified over a decade ago, the physiological function(s) of the protein and the molecular mechanism(s) for its biological activities are still an area of active investigation. Neuromodulin has been implicated in several biological processes in neurons, including growth and regeneration, synaptic plasticity and neurotransmitter release. The molecular mechanisms underlying these implied physiological roles have not been elucidated, but there are several molecular properties of neuromodulin that may be important for its function in neurons. In this review, we will discuss research which has defined several of the functional domains of neuromodulin, including its phosphorylation sites, calmodulin binding domain, membrane binding domain and growth cone targeting domain. We will also suggest possible molecular functions of neuromodulin based on its biochemical properties.

Amino Acid Sequence↗
PubMed1992

The downregulation of growth-associated proteins in motoneurons at the onset of synapse elimination is controlled by muscle activity and IGF1.

Axonal growth during development and regeneration coincides with the expression of growth-associated proteins (GAPs), including GAP-43 and tubulin-alpha 1. Following contact with the target region and synaptogenesis, GAPs are downregulated. However, high levels of GAP-43 are expressed in some neurons in the adult CNS, indicating that its function may not be restricted to axonal growth. To define the type of signals that regulate GAP levels during development, we have determined whether GAP downregulation coincides with a defined phase of synapse development and whether it is controlled by the postsynaptic target. Levels of GAP-43 mRNA in spinal motoneurons and protein at the neuromuscular junction were analyzed in the developing neuromuscular system of chick and rat. In both species, GAP-43 mRNA declined rapidly at a time corresponding to the onset of synapse elimination, and nerve terminal GAP-43 immunoreactivity became undetectable with a delay of 2-3 d. In rat motoneurons, GAP-43 and tubulin-alpha 1 mRNA levels declined with a similar time course, indicating that at least two GAPs are downregulated at the same time. Blockade of neuromuscular transmission with either a pre- or a postsynaptically acting toxin prevented GAP downregulation, indicating that target activity affects GAP mRNA levels in motoneurons. Finally, counteracting the activity-dependent decline of muscle insulin-like growth factors during synapse elimination by local subcutaneous injections prevented motoneuron GAP downregulation, suggesting that these growth factors may be involved in the regulation of motoneuron GAPs by the muscle. These results demonstrate that motoneurons undergo target-sensitive changes in GAPs at the onset of synapse elimination. In addition, these results raise the possibility that termination of a presynaptic growth mode may be a prerequisite for synapse elimination.

Animals↗
PubMed1992

Involvement of growth-associated protein-43 with irreversible neurite outgrowth by dibutyryl cyclic AMP and phorbol ester in NG108-15 cells.

Simultaneous treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) and dibutyryl cyclic AMP (diBu-cAMP) for 72 h induced neurites in NG108-15 cells significantly longer than treatment with each alone. Treatment for 72 h with both drugs induced irreversible neurite extension and a decline in protein kinase C activity, although neurites extended by diBu-cAMP alone disappeared after the withdrawal of the drug. The expression of growth-associated protein-43 (GAP-43) mRNA was also observed by a combined application of TPA and diBu-cAMP. The increased level of GAP-43 mRNA induced by treatment with both drugs for 72 h was maintained at least 24 h after withdrawal of the drugs. In cells transfected with GAP-43 cDNA, neurites induced by treatment with diBu-cAMP alone for 72 h were maintained at least 48 h after removal of the drugs. These results suggest that GAP-43 could be involved in the maintenance of elongated neurites and that a decline in protein kinase C activity may be involved in the accumulation of GAP-43.

Animals↗
PubMed1992

GAP-43 expression in macroglial cells: potential functional significance.

Although growth-associated protein-43 (GAP-43) was initially considered to be neuron-specific, it has more recently been found in astrocytes, oligodendrocytes, Schwann cells, glial cell equivalents in embryonic Drosophila and other non-neuronal cells. Here I summarize evidence for the presence of GAP-43 in macroglial cells (i.e., astrocytes and oligodendrocytes) cultured from neonatal rat cortex and describe its developmental expression in a lineage-specific and cell-type-specific manner. These and other data suggest that GAP-43 is a multifunctional protein involved in the synthesis of membranes associated with the growth of various types of cellular processes, including those of macroglial cells.

Animals↗