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Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The decline in CD4/CD8 ratios in lymph nodes (LNs) of SIV macaques and HIV-infected individuals occurs later than that in blood. In a previous study, long-term SIV-infected macaques were delineated into two groups: (1) those whose LNs had normal CD4/CD8 ratios and (2) those whose LNs had low CD4/CD8 ratios. In the present investigation, LNs, spleens, and blood from these groups have been further analyzed to ascertain the cellular and virological events, particularly those involving CD8+ cells, that occur concomitantly with LN CD4% decline. An increase in the percent of CD69-, IL-2R(p75)-, CD45RA1o CD8+ cells was the most constant event observed in lymphoid tissue from mid- to late-stage SIV-infected monkeys. Such cells were sometimes observed in LNs prior to any other immunological or morphological changes. However, decline in LN CD4/CD8 ratios and the associated degeneration of follicular dendritic cells (FDCs) in the germinal centers (GCs) of these nodes were observed only when both CD8+ cell infiltration of GCs and accumulation of viral antigens within the FDC network could be demonstrated. These dramatic changes were also associated with significantly reduced responsiveness to mitogens throughout the lymphoid compartment. In terms of viral burden, immunological and structural collapse of LNs was not always associated with increased viral DNA levels. Despite the CD4+ cell decline in blood during HIV and SIV infections, the immunological and architectural collapse of the lymphoid compartment, which comprises the bulk of the lymphocytes in the body, appears to be a critical event leading to the onset of AIDS. The present findings suggest that increased CD8+ cell activity as well as decrease in CD4+ cell function both contribute to this process.
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PMID:Immunological and virological changes associated with decline in CD4/CD8 ratios in lymphoid organs of SIV-infected macaques. 798 91

Multiple factors are involved in the development and regulation of sensory innervation in skin. The findings we report here suggest that brain-derived neurotrophic factor (BDNF)-mediated inhibition may play an important role in determining the pattern of sensory innervation in avian skin. In birds, cutaneous innervation is restricted to dermis, where axons form a ring of innervation around the base of each feather. Here we show that both BDNF message and protein are more abundant in avian epidermis than dermis when innervation is being established; the BDNF in dermis is localized to feather buds. In vitro, BDNF caused growth cones of NGF-dependent dorsal root ganglion neurons to collapse. Similarly, outgrowth of neurites toward BDNF-secreting fibroblasts was inhibited. The inhibitory effects of BDNF appear to be mediated by the low-affinity p75 neurotrophin receptor, rather than a trk receptor. Thus, the distribution of BDNF in embryonic avian skin and the inhibitory effects of BDNF on cutaneous neurites in vitro suggest that BDNF may be important in restricting axons from entering the epidermis and the core of feather buds during development in vivo.
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PMID:Contribution of BDNF-mediated inhibition in patterning avian skin innervation. 1125 61

At least three proteins present in CNS myelin, Nogo, MAG and OMgp are capable of causing growth cone collapse and inhibiting neurite outgrowth in vitro. Surprisingly, Nogo and OMgp are also strongly expressed by many neurons (including neocortical projection cells). Nogo expression is increased by some cells at the borders of CNS lesion sites and by cells in injured peripheral nerves, but Nogo and CNS myelin are largely absent from spinal cord injury sites, which are none the less strongly inhibitory to axonal regeneration. Nogo is found on growing axons during development, suggesting possible functions for neuronal Nogo in axon guidance. Although Nogo, MAG and OMgp lack sequence homologies, they all bind to the Nogo receptor (NgR), a GPI-linked cell surface molecule which, in turn, binds p75 to activate RhoA. NgR is strongly expressed by cerebral cortical neurons but many other neurons express NgR weakly or not at all. Some neurons, such as DRG cells, respond to Nogo and CNS myelin in vitro although they express little or no NgR in vivo which, with other data, indicates that other receptors are available for NgR ligands. NgR expression is unaffected by injury to the nervous system, and there is no clear correlation between NgR expression by neurons and lack of regenerative ability. In the injured spinal cord, interactions between NgR and its ligands are most likely to be important for limiting regeneration of corticospinal and some other descending tracts; other receptors may be more important for ascending tracts. Antibodies to Nogo, mainly the poorly-characterised IN-1 or its derivatives, have been shown to enhance recovery from partial transections of the spinal cord. They induce considerable plasticity from the axons of corticospinal neurons, including sprouting across the midline and, to a limited extent, regeneration around the lesion. Regeneration of corticospinal axons induced by Nogo antibodies has not yet been demonstrated after complete transections or contusion injuries of the spinal cord. It is not clear whether antibodies against Nogo act on oligodendrocytes/myelin or by binding to neuronal Nogo, or whether they can stimulate regeneration of ascending axons in the spinal cord, most of which express little or no NgR. Despite these uncertainties, however, NgR and its ligands offer important new targets for enhancing plasticity and regeneration in the nervous system.
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PMID:The Nogo receptor, its ligands and axonal regeneration in the spinal cord; a review. 1281 33

The motile behaviors of growth cones at the ends of elongating axons determine pathways of axonal connections in developing nervous systems. Growth cones express receptors for molecular guidance cues in the local environment, and receptor-guidance cue binding initiates cytoplasmic signaling that regulates the cytoskeleton to control growth cone advance, turning, and branching behaviors. The dynamic actin filaments of growth cones are frequently targets of this regulatory signaling. Rho GTPases are key mediators of signaling by guidance cues, although much remains to be learned about how growth cone responses are orchestrated by Rho GTPase signaling to change the dynamics of polymerization, transport, and disassembly of actin filaments. Binding of neurotrophins to Trk and p75 receptors on growth cones triggers changes in actin filament dynamics to regulate several aspects of growth cone behaviors. Activation of Trk receptors mediates local accumulation of actin filaments, while neurotrophin binding to p75 triggers local decrease in RhoA signaling that promotes lengthening of filopodia. Semaphorin IIIA and ephrin-A2 are guidance cues that trigger avoidance or repulsion of certain growth cones, and in vitro responses to these proteins include growth cone collapse. Dynamic changes in the activities of Rho GTPases appear to mediate responses to these cues, although it remains unclear what the changes are in actin filament distribution and dynamic reorganization that result in growth cone collapse. Growth cones in vivo simultaneously encounter positive and negative guidance cues, and thus, growth cone behaviors during axonal pathfinding reflect the complex integration of multiple signaling activities.
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PMID:Regulation of growth cone actin filaments by guidance cues. 1459 73

After binding, central nervous system (CNS) myelin-derived axon growth inhibitory ligands, the Nogo-66 receptor (NgR), complexes with LINGO-1 and either the low-affinity neurotrophin receptor (p75(NTR)) or TROY to initiate growth cone collapse via a Rho-A inhibitory signaling pathway and/or Ca(2+)-dependent activation of epidermal growth factor receptor (EGFR) through an unknown signaling pathway. We have shown that axon growth through CNS myelin is disinhibited after neurotrophic factor administration by 1) initiating intramembranous proteolysis (RIP) of p75(NTR), leading to cleavage of the extracellular (p75(ECD)) and intracellular domains (p75(ICD)) by alpha- and gamma-secretase, respectively, thereby paralyzing inhibitory signaling; 2) shedding of soluble NgR(ECD), which acts as a competitive antagonist to NgR for binding of inhibitory ligands; and 3) antagonizing NgR/p75(NTR) clustering by competitive p75(ECD)/NgR interaction. Here, we report that TNF-alpha converting enzyme (TACE) (a disintegrin and metalloproteinase 17, ADAM17) induces disinhibition of FGF2-stimulated neurite outgrowth of dorsal root ganglion neurons (DRGN) cultured in the presence of a predetermined concentration of inhibitory CNS myelin-derived ligands. After addition of TACE (which has alpha-secretase activity) to mitotically arrested adult rat mixed DRG cultures, we demonstrate 1) NgR(ECD) shedding; 2) release of p75(ECD) and p75(ICD) by RIP of p75(NTR); 3) blockade of Rho-A activation; 4) reduced EGFR phosphorylation; and 5) increased FGF2-stimulated DRGN neurite outgrowth and branching in the presence of CNS myelin-derived inhibitory ligands. Thus, TACE-induced cleavage of NgR and RIP of p75(NTR) abrogates axon growth inhibitory signaling, thereby disinhibiting CNS axon/neurite growth.
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PMID:TACE-induced cleavage of NgR and p75NTR in dorsal root ganglion cultures disinhibits outgrowth and promotes branching of neurites in the presence of inhibitory CNS myelin. 1684 93

The neurotrophin receptor p75 (p75NTR) is expressed by both neurons and glia. Nerve injury triggers up-regulation of p75NTR in Schwann cells (SC) but not in central glia. In contrast to neuronal p75NTR, which mediates negative signals from myelin-associated proteins resulting in neurite collapse, glial p75NTR may play a positive role in nerve regeneration by forming neurotrophin chemoattractant gradients or by competitively antagonizing the NOGO/NgR/LINGO-1 signal through cell-cell contact or regulated intramembranous proteolysis (RIP) of p75NTR. This piece presents some recent evidence supporting this hypothesis.
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PMID:Roles of glial p75NTR in axonal regeneration. 1733 80

In the adult mammalian central nervous system (CNS), it is well known that injured axons exhibit very limited regeneration ability. Due to this lack of appropriate axonal regeneration, a traumatic damage to the adult brain and spinal cord frequently causes permanent neuronal deficits such as paralysis. Several axon growth inhibitors, including myelin-associated glycoprotein, Nogo, and oligodensrocyte myelin glycoprotein, in the CNS have been identified in the myelin. Receptor complex comprising of the Nogo receptor, the p75 receptor, and LINGO-1 transduces the signals from all of these inhibitors in vitro. Downstream of these inhibitors, activation of small GTPase RhoA and its effector Rho-kinase has been shown to be a key element for neurite growth inhibition and growth cone collapse elicited by these inhibitors. Consistent with these findings in vitro, inhibition of RhoA or Rho-kinase in vivo promotes axon growth and functional recovery after spinal cord injury. Recently, several developmental guidance proteins, including repulsive guidance molecules, semaphorin, and ephrin are suggested to be involved in axon growth inhibition after injury to the CNS. Thus, multiple axon growth inhibitors seem to contribute to inability of the injured axons to regenerate, and therapeutic strategy to block the multiple axon growth inhibitors may provide efficient tools that produce functional regeneration following injuries to the CNS. In addition, it is noted that synaptic plasticity in pre-existing pathways and the formation of new circuits through collateral sprouting of lesioned and unlesioned fibers are important components of the spontaneous recovery process. The molecular mechanism of this phenomenon is poorly understood, and elucidation of this will contribute to enhancement of functional recovery after incomplete injury to the CNS. I will summarize recent findings regarding these issues.
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PMID:[Molecular mechanism and regulation of axon growth inhibition]. 1809 84

Many chemotherapy drugs are known to cause significant clinical neurotoxicity, which can result in the early cessation of treatment. To identify and develop more effective means of neuroprotection it is important to understand the toxicity of these drugs at the molecular and cellular levels. In the present study, we examine the effects of paclitaxel (taxol), cisplatin, and methotrexate on primary rat neurons including hippocampal, cortical, and dorsal horn/dorsal root ganglion neuronal cultures. We found that all of these anti-cancer drugs induce substantial neurotoxicity evidenced by neurite degeneration. The neurons are capable of recovering after treatment withdrawal, but taxol exerts a biphasic effect that results in the collapse of processes days after treatment is withdrawn. After cisplatin and methotrexate treatment, we observed the degeneration of neuronal processes including the reduction of dendritic branching, length, and altered growth cone formation, indicating an abnormal arrangement of the actin cytoskeleton consistent with the involvement of Rho family small GTPases. Inhibiting RhoA downstream effector p160 ROCK/Rho kinase using Y-27632, or activating p75 neurotrophin receptor (p75 NTR) using non-peptide mimetic LM11A-31, were able to reverse the degeneration caused by cisplatin and methotrexate. Therefore, the neurotoxicity resulting from exposure to the anti-cancer drugs cisplatin and methotrexate can be alleviated by inhibiting Rho signaling pathway.
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PMID:Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants. 1853 32

The p75 neurotrophin receptor (p75NTR) is a transmembrane protein that binds nerve growth factor (NGF) and has multiple functions in the nervous system where it is expressed widely during the developmental stages of life, although expression decreases dramatically by adulthood. Expression of p75NTR can increase in pathological states related to neural cell death. p75NTR is a member of the tumour necrosis factor (TNF) receptor family and it consists of intracellular, transmembrane and extracellular domains which are different from other TNF receptors. Either by interacting with tropomyosin receptor kinase (Trk) receptors or via the independent binding of neurotrophin, p75NTR can induce neurite outgrowth and cellular survival or cell apoptosis through several complicated signal transduction pathways. Most of these signalling pathways remain to be elucidated. By interacting with different cellular factors, p75NTR can induce neuron growth cone collapse or regrowth. p75NTR is also expressed in a variety of glial populations. The many functions of p75NTR require further study.
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PMID:Multiple roles of the p75 neurotrophin receptor in the nervous system. 1938 20

The intercellular cell adhesion molecule-1 (ICAM-1) has been implicated in the recruitment of immune cells during inflammatory processes. Previous studies investigating its involvement in the process of Wallerian degeneration and focusing on its potential role in macrophage recruitement have come to controversial conclusions. To examine whether Wallerian degeneration is altered in the absence of ICAM-1, we have analyzed changes in the expression of axonal and Schwann cell markers following sciatic nerve crush in wildtype and ICAM-1-deficient mice. We report that the lack of ICAM-1 leads to impaired axonal degeneration and regeneration and to alterations in Schwann cell responses following sciatic nerve crush. Degradation of neurofilament protein, the collapse of axonal profiles, and the re-expression of neurofilament proteins are substantially delayed in the distal nerve segment of ICAM-1(-/-) mice. In contrast, the degradation of myelin, as determined by immunostaining for myelin protein zero, is unaltered in the mutants. Upregulation of GAP-43 and p75 neurotrophin receptor (p75(NTR)) expression, characteristic for Schwann cells dedifferentiating in response to nerve injury, is differentially altered in the mutant animals. These results indicate that ICAM-1 is essential for the normal progression of axonal degeneration and regeneration in distal segments of injured peripheral nerves.
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PMID:Wallerian degeneration and axonal regeneration after sciatic nerve crush are altered in ICAM-1-deficient mice. 1965 76


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