GAP-43 expression in the medulla of macaque monkeys: changes during postnatal development and the effects of early median nerve repair.
TL;DR: The results suggest that reorganization mechanisms at central terminals of peripheral nerves are very different following prenatal than postnatal nerve damage.
About: This article is published in Developmental Brain Research.The article was published on 1995-12-21. It has received 7 citations till now. The article focuses on the topics: Macaque & Cuneate nucleus.
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TL;DR: The assumption that congenital absence of a limb does not lead to cortical reorganization or phantom limbs is confirmed whereas traumatic amputations that are accompanied by phantom limb pain show shifts of the cortical areas adjacent to the amputation zone towards the representation of the deafferented body part.
Abstract: The extent of the cortical somatotopic map and its relationship to phantom phenomena was tested in five subjects with congenital absence of an upper limb, four traumatic amputees with phantom limb pain and five healthy controls. Cortical maps of the first and fifth digit of the intact hand, the lower lip and the first toe (bilaterally) were obtained using neuroelectric source imaging. The subjects with congenital upper limb atrophy showed symmetric positions of the left and right side of the lower lip and the first toe, whereas the traumatic amputees with pain showed a significant shift (about 2.4 cm) of the cortical representation of the lower lip towards the hand region contralateral to the amputation side but no shift for the toe representation. In healthy controls, no significant hemispheric differences between the cortical representation of the digits, lower lip or first toe were found. Phantom phenomena were absent in the congenital but extensive in the traumatic amputees. These data confirm the assumption that congenital absence of a limb does not lead to cortical reorganization or phantom limbs whereas traumatic amputations that are accompanied by phantom limb pain show shifts of the cortical areas adjacent to the amputation zone towards the representation of the deafferented body part.
142 citations
TL;DR: It is shown that there is little or no topographic order in the median nerve to the hand after median nerve section and surgical repair in immature macaque monkeys, and in the same animals the representation of the reinnervated hand in primary somato-sensory cortēx is quite orderly.
Abstract: Transection of a sensory nerve in adults results in profound abnormalities in sensory perception, even if the severed nerve is surgically repaired to facilitate accurate nerve regeneration. In marked contrast, fewer perceptual errors follow nerve transection and surgical repair in children. The basis for this superior recovery in children was unknown. Here we show that there is little or no topographic order in the median nerve to the hand after median nerve section and surgical repair in immature macaque monkeys. Remarkably, however, in the same animals the representation of the reinnervated hand in primary somatosensory cortex area (area 3b) is quite orderly. This indicates that there are mechanisms in the developing brain that can create cortical topography, despite disordered sensory inputs. Presumably the superior recovery of perceptual abilities after peripheral nerve transection in children depends on this restoration of somatotopy in the central sensory maps.
91 citations
TL;DR: The combined results suggest that the early phase of regeneration of peripheral nerves in the presence of peptide‐incorporated collagen tubes results in the enhanced production of trophic factors by the recruited hematogenous cells and Schwann cells, which in turn help in the secretion of certain vital Trophic and tropic factors essential for early regeneration.
Abstract: Neurotrophic factors play an important modulatory role in axonal sprouting during nerve regeneration involving the proliferation of hematogenous and Schwann cells in damaged tissue. We have exposed lesioned sciatic nerves to a collagen prosthesis with covalently bonded small cell adhesive peptides Arg-Gly-Asp-Ser (RGDS), Lys-Arg-Asp-Ser (KRDS), and Gly-His-Lys (GHK) to study local production of growth factors and cytokines in the regenerating tissues. Western/enzyme-linked immunosorbent assay (ELISA) studies were performed after 10 days of regeneration, when the tubular prosthesis is filled with fibrous matrix infiltrated by hematogenous cells and proliferating Schwann cells with growth factors produced locally. Regeneration was also analyzed by morphometrical methods after 30 days. The quantification of growth factors and proteins by ELISA revealed that there was an enhanced expression of the neurotrophic factors nerve growth factor (NGF) and neurotrophins (NT-3 and NT-4) in the regenerating tissues. This was further established by Western blot to qualitatively analyze the presence of the antigens in the regenerating tissues. Schwann cells were localized in the regenerating tissues using antibodies against S-100 protein. Other growth factors including growth-associated protein 43 (GAP-43), apolipoprotein E (Apo E), and pro-inflammatory cytokine like interleukin-1alpha (IL-1alpha) expression in the peptide groups were evaluated by ELISA and confirmed by Western blotting. Cell adhesive integrins in the proliferating cells were localized using integrin-alpha V. The combined results suggest that the early phase of regeneration of peripheral nerves in the presence of peptide-incorporated collagen tubes results in the enhanced production of trophic factors by the recruited hematogenous cells and Schwann cells, which in turn help in the secretion of certain vital trophic and tropic factors essential for early regeneration. Furthermore, hematogenous cells recruited within the first 10 days of regeneration help in the production of inflammatory mediators like interleukins that in turn stimulate Schwann cells to produce NGF for axonal growth.
29 citations
Cites background from "GAP-43 expression in the medulla of..."
...The expression of GAP-43, a neuronal-specific growth-associated phosphoprotein, has been highly correlated with the growth and remodeling of the nervous system during development and regeneration (Jain et al., 1995)....
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TL;DR: GAP43 expression is involved in timing of muscle maturation in-vivo, and the emerging hypothesis indicates that GAP43 interacts with calmodulin to indirectly modulate the activities of dihydropyridine and ryanodine Ca2+ channels, from functional excitation-contraction coupling, to cell metabolism, and gene expression.
Abstract: Neuronal growth-associated protein 43 (GAP43) has crucial roles in the nervous system, and during development, regeneration after injury, and learning and memory. GAP43 is expressed in mouse skeletal muscle fibers and satellite cells, with suggested its involvement in intracellular Ca2+ handling. However, the physiological role of GAP43 in muscle remains unknown. Using a GAP43-knockout (GAP43-/-) mouse, we have defined the role of GAP43 in skeletal muscle. GAP43-/- mice showed low survival beyond weaning, reduced adult body weight, decreased muscle strength, and changed myofiber ultrastructure, with no significant differences in the expression of markers of satellite cell and myotube progression through the myogenic program. Thus GAP43 expression is involved in timing of muscle maturation in-vivo. Intracellular Ca2+ measurements in-vitro in myotubes revealed GAP43 involvement in Ca2+ handling. In the absence of GAP43 expression, the spontaneous Ca2+ variations had greater amplitudes and higher frequency. In GAP43-/- myotubes, also the intracellular Ca2+ variations induced by the activation of dihydropyridine and ryanodine Ca2+ channels, resulted modified. These evidences suggested dysregulation of Ca2+ homeostasis. The emerging hypothesis indicates that GAP43 interacts with calmodulin to indirectly modulate the activities of dihydropyridine and ryanodine Ca2+ channels. This thus influences intracellular Ca2+ dynamics and its related intracellular patterns, from functional excitation-contraction coupling, to cell metabolism, and gene expression.
16 citations
Cites background or result from "GAP-43 expression in the medulla of..."
...The levels of GAP43 expression are critical not only for nervous system development and growth (Jain et al., 1995; Murata et al., 2005), but also for skeletal muscle development after birth....
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...Furthermore, as other studies have also reported for specific areas of neuronal tissue (Jain et al., 1995; Murata et al., 2005), in the WT mice, from birth to old age, the GAP43 expression decreased whenmuscle maturation was complete (i.e., at 1 to 4 months old) and remained low during old age…...
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TL;DR: The ability to adjust to changes in the external environment is critical for learning and for recovery from brain injury as discussed by the authors, and the ability to respond in a reliable way is crucial for learning.
Abstract: Two basic features of our brains seem almost incompatible with each other One feature is the processing of information in a predictable and reliable manner In order to do this, one would suppose that the machinery of the brain, the local circuits and processing pathways, would be morphologically and functionally stable, at least in adults Yet, the second feature-the ability to adjust to changes in the external environment-is critical for learning and for recovery from brain injury How can circuits change and yet allow us to respond in a reliable way? Many investigators resolved this quandary by assuming that although most circuits in the brain
9 citations
References
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TL;DR: The results of studies directed toward determining the time course and likely mechanisms underlying this remarkable plasticity of the cortex representing the skin of the median nerve within parietal somatosensory fields 3b and 1 are described.
725 citations
TL;DR: It is proposed that some step(s) in axon growth require production of GAP-43, and perhaps a small number of other “growth-associated proteins,” at rates much higher than those typical of mature neurons, and this hypothesis predicts that virtually all neurons synthesize G AP-43 at elevated levels during normal CNS development.
Abstract: Development or regeneration of axons in several systems is accompanied by 20-100-fold increases in the synthesis of an acidic, axonally transported membrane protein with an apparent molecular weight of 43-50,000 (Benowitz and Lewis, 1983; Skene and Willard, 1981a, b), which we designate GAP-43. We have proposed that some step(s) in axon growth require production of GAP-43, and perhaps a small number of other "growth-associated proteins," at rates much higher than those typical of mature neurons. This hypothesis predicts that virtually all neurons synthesize GAP-43 at elevated levels during normal CNS development. Here we show that a protein similar to GAP-43 from regenerating toad nerves is prominent among the newly synthesized (35S-methionine-labeled) and total (Coomassie blue-stained) proteins in neonatal rat cerebral cortex and cerebellum, suggesting that synthesis of GAP-43 is indeed a common feature of many developing neurons. Synthesis and accumulation of the protein decline an order of magnitude as animals mature. Antibodies raised against the rat cortex GAP-43 also recognize electrophoretically similar proteins from regenerating toad optic nerves and from developing hamster sensorimotor cortex, indicating that structural features of GAP-43 are conserved in evolution. Cell-free translation of polyadenylated RNA from neonatal and adult cortex suggests that developmental regulation of GAP-43 synthesis is mediated largely through changes in mRNA abundance. These observations together suggest that developmental regulation of GAP-43 gene expression may be common to most vertebrate CNS neurons. GAP-43 remains detectable at a low level in adult rat cortex, and it co-migrates on two-dimensional gels with B-50, a synaptic membrane protein which is a preferred substrate for protein kinase C in adult brains. Phosphorylation of the protein by endogenous kinase(s) in vitro is 4-7-fold greater in growth cone membranes than in mature synaptic membranes, which raises the possibility that local modification of the protein in axon terminals may be synergistic with regulation of GAP-43 synthesis in the cell body.
438 citations
TL;DR: This distributional pattern raises the question of whether synapses in all areas containing high levels of GAP-43/B-50 are capable of undergoing functional plasticity, or whether the protein may function in some of these areas in some other capacity.
Abstract: GAP-43 (B-50,F1,pp46) is a neuron-specific phosphoprotein that has been implicated in the development and modulation of synaptic relationships. Although most neurons cease expressing high levels of GAP-43 after the completion of synaptogenesis (Jacobson et al., 1986), certain brain regions continue to have considerable amounts of the protein throughout life (Oestreicher et al., 1986); in at least one such area, the phosphorylation of the protein has been linked with the events that underlie synaptic potentiation (Lovinger et al., 1985). In this study, we used the indirect immunoperoxidase method to map the distribution of GAP-43/B-50 in the brains of 8 adult rats with 2 different antibodies: a monospecific, polyclonal antibody prepared in sheep against the purified protein and an affinity-purified IgG prepared in rabbits. Specific immunoreactivity was found primarily in the neuropil and followed a generally increasing caudal-to-rostral gradient along the neuraxis. Densest staining occurred in layer I of the cortex, the CA1 field of the hippocampus, and in a continuum of subcortical structures that included the caudate-putamen, olfactory tubercle, nucleus accumbens, bed nucleus of the stria terminalis, amygdala, and medial preoptic area-hypothalamus. In the brain stem, staining was seen in the central gray and in ascending visceral relay nuclei, but was essentially absent in areas related to ascending somatosensory information (e.g., the cochlear nuclei or vestibular complex) and motor control (e.g., nucleus ruber or the motor nuclei of the cranial nerves). Staining in dorsal thalamus was likewise modest in most somatosensory and somatomotor relay nuclei, but dark in certain other structures (e.g., mediodorsal nucleus, lateral complex). This distributional pattern raises the question of whether synapses in all areas containing high levels of GAP-43/B-50 are capable of undergoing functional plasticity, or whether the protein may function in some of these areas in some other capacity (e.g., general signal transduction).
396 citations
TL;DR: GAP-43 is one of a small subset of cellular proteins selectively transported by a neuron to its terminals, and its enrichment in growth cones and its increased levels in developing or regenerating neurons suggest that it has an important role in neurite growth.
Abstract: GAP-43 is one of a small subset of cellular proteins selectively transported by a neuron to its terminals. Its enrichment in growth cones and its increased levels in developing or regenerating neurons suggest that it has an important role in neurite growth. A complementary DNA (cDNA) that encodes rat GAP-43 has been isolated to study its structural characteristics and regulation. The predicted molecular size is 24 kilodaltons, although its migration in SDS-polyacrylamide gels is anomalously retarded. Expression of GAP-43 is limited to the nervous system, where its levels are highest during periods of neurite outgrowth. Nerve growth factor or adenosine 3',5'-monophosphate induction of neurites from PC12 cells is accompanied by increased GAP-43 expression. GAP-43 RNA is easily detectable, although at diminished levels, in the adult rat nervous system. This regulation of GAP-43 is concordant with a role in growth-related processes of the neuron, processes that may continue in the mature animal.
339 citations
TL;DR: In the CNS the elevated GAP-43 levels may contribute to an inappropriate synaptic reorganization of afferent terminals that could play a role in the sensory disorders that follow nerve injury.
334 citations