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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Precursors from the neuroepithelium of the developing cortex and the adult subventricular zone can be cloned in vitro after stimulation with fibroblast growth factor 2 (FGF-2), and they have the potential to give rise to both neurons and glia. The generation of neurons from these clones can be stimulated by either a factor derived from an astrocyte precursor line, Ast-1, or FGF-1. We have shown that neuronal differentiation stimulated by FGF-1 can be inhibited by diacylglycerol lipase inhibitor and mimicked by arachidonic acid, suggesting that the neuronal differentiation is signalled through the phospholipase C gamma pathway. The sequential expression of FGF-2, followed by FGF within the developing forebrain neuroepithelium, fits with the different functions that the two FGFs play in precursor regulation. We have shown that the precursor response to FGF-1 is regulated by a heparan sulphate proteoglycan expressed within the developing neuroepithelium. Precursors restricted to the astrocyte cell lineage can be stimulated by epidermal growth factor or FGF-2F however, the differentiation into glial fibrillary acidic protein-positive astrocytes appears to require a cytokine acting through the leukaemia inhibitory factor-beta receptor.
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PMID:Factors regulating the differentiation of neural precursors in the forebrain. 872 88

Newborn F344 rats were injected intraperitoneally with PVC441 virus, a neuropathogenic variant of Friend murine leukemia virus, and developed paraparesis of hind limbs 35-40 days after infection. Immunohistochemical study using monoclonal anti-PVC441 antibody revealed that in the central nervous system endothelial cells but not neuronal or glial cells were infected with PVC441 virus. The major pathological changes were myelin vacuolation and oligodendrocyte degeneration in the white matter at the white-gray border zone. Anterior and lateral funiculi and intercalated myelin of anterior horns were dominantly affected in the spinal cord from the sacral to cervical level. The midbrain was also vacuolated. An ultrastructural study demonstrated that many viral particles were present outside the endothelial cells but only sparsely inside endothelial cells and pericytes. Endothelial cell membranes and tight junctions were also disrupted. Immunohistochemical studies with antibodies against major histo-compatibility complex class Ia, intercellular adhesion molecule-I, glial fibrillary acidic protein, neurofilament protein, CD3 and OX42 revealed the presence of abundant microglia but not of lymphocytes or polymorphonuclear cells in the lesions. Axonal degeneration and astrogliosis were mild in degree. These pathological changes explain the observed spastic paraparesis in the rats, and represent a good model of spongiform diseases of the human central nervous system of retroviral origin, such as human T cell leukemia virus-associated myelopathy and AIDS.
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PMID:Central nervous system lesions in rats infected with Friend murine leukemia virus-related PVC441: ultrastructural and immunohistochemical studies. 911 2

Mice infected with the LP-BM5 murine leukemia virus (MuLV) mixture develop severe immunosuppression, neurotransmitter abnormalities and cognitive impairments in the absence of significant viral or macrophage invasion of the CNS. The time-course of the changes in glial activation have been characterized in an effort to understand the cellular basis of the neurobehavioral abnormalities observed in these mice. Glial activation was determined by measuring the relative changes in F4/80 protein and GFAP immunoreactivity using immunoblots. Augmented F4/80 expression preceded that of GFAP, with global elevations of 4-6-fold at 3 weeks, sustained for up to 12 weeks after inoculation. GFAP immunoreactivity increased 2-fold only in the cerebral cortex and striatum 5 weeks postinfection, declining to control levels by 12 weeks. Immunohistochemistry revealed significant increases in microglial size and staining intensity in the cortex, corpus callosum and striatum, with the development of a unique population of highly ramified, intensely stained microglia and microglial nodules in the corpus callosum and striatum. No evidence of ameboid microglia was found. Astrocyte size and degree of ramification was increased in the hippocampus, cortex, striatum and corpus callosum. Thus, microgliosis is an early event in LP-BM5 infection, preceding astrocytosis, neurotransmitter loss, and development of cognitive deficits. Activated microglia may secrete neurotoxins leading to the neurochemical alterations and cognitive deficits observed in these mice. Because gliosis and microglial nodule formation are hallmarks of HIV-1 encephalopathy, LP-BM5 MuLV-infected C57/B16 mice may afford insights into the mechanisms contributing to the early stages of this syndrome.
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PMID:Gliosis in the LP-BM5 murine leukemia virus-infected mouse: an animal model of retrovirus-induced dementia. 911 5

The cytopathic infection of primary astrocytes with ts1, a neuroimmunopathogenic mutant of Moloney murine leukemia virus (MuLV), has been correlated to intracellular accumulation of viral precursor envelope protein gPr80env. To further study this specific virus-astrocyte interaction in a homogenous population, several immortal astrocyte lines were established from neonatal FVB/N mice using the temperature-sensitive SV40 tsA58 T antigen. These cells expressed glial fibrillary acidic protein, vimentin and T antigen; appeared nontransformed; were star-shape with long processes. They were susceptible to ts1 infection and suffered a cytopathic effect similar to that caused by ts1 infection of primary astrocytes. This cytopathic effect was characterized by growth inhibition, loss of cell processes and syncytium formation. Some cells also rounded up, formed mini cells and became detached from the culture dish. As in primary astrocytes, the processing of gPr80env in the immortalized astrocytes was inefficient. Since the envelope proteins interact with the ecotropic MuLV receptor both intracellularly and on the cell surface and since the receptor has been shown to be an arginine transporter, we attempted to determine the effect of ts1 on arginine uptake by these cells. Our results showed that in both immortalized and primary astrocytes, ts1 infection reduced the uptake of arginine more than did wild-type virus infection. Since arginine localizes predominantly in astrocytes in the CNS and has diverse functions, the decrease of arginine uptake in ts1-infected astrocytes may alter the metabolism of these cells, leading to impairment of their functions.
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PMID:Establishment and characterization of conditionally immortalized astrocytes to study their interaction with ts1, a neuropathogenic mutant of Moloney murine leukemia virus. 914 19

Replication-defective Moloney murine leukemia virus expressing the GAD67 gene under the control of the GFAP promoter was produced using selected clones of a fibroblast-packaging cell line. A spontaneously immortalized astrocyte cell line was infected with this virus and cellular clones expressing GAD67 selected. Astrocyte and fibroblast clones expressed functional GAD (detected by glutamic acid decarboxylation), but only fibroblasts were able to also produce GABA in the extracellular medium. When exposed to 200 microM glutamate, despite an observed difference in the rates of glutamate accumulation in control and GAD67-expressing astrocytes, similar proportions of glutamate taken up were detected. In GAD67-expressing astrocytes, the glutamate was mainly converted into GABA, suggesting GAD transgene activity to be dominant over other glutamate metabolic pathways, such as glutamine synthetase and glutamate dehydrogenase. Moreover, rapid GABA release into the cell medium was also observed, suggesting the involvement of reverse GABA transporters. The use of the GFAP promoter might be able to take advantage of its activation in response to factors inducing reactive gliosis observed in pathological insults. GAD67-expressing astrocytes might therefore be used for future grafting in pathological situations in which an excess of glutamate results in neuronal dysfunction or cell death.
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PMID:Glutamate-modulated production of GABA in immortalized astrocytes transduced by a glutamic acid decarboxylase-expressing retrovirus. 943 90

In the developing forebrain, mounting evidence suggests that neural stem cell proliferation and differentiation is regulated by growth factors. In vitro in the presence of serum, stem cell proliferation is predominantly mediated by fibroblast growth factor-2 (FGF-2) whereas neuronal differentiation can be triggered by FGF-1 in association with a specific heparan sulphate proteoglycan. On the other hand, astrocyte differentiation in vivo and in vitro appears to be dependent on signalling through the leukaemia inhibitory factor receptor (LIFR). The evidence suggests that in the absence of LIFR signalling, the stem cell population is present at approximately the same frequency and can generate neurons but is blocked from producing astrocytes that express glial fibrillary acidic protein (GFAP) or have trophic functions. The block can be overcome by other growth factors such as BMP-2/4 or interferon-gamma, providing further evidence that the inhibition to astrocyte development does not result from loss of a precursor population. Signalling through the LIFR, in addition to stimulating astrocyte differentiation, may also inhibit neuronal differentiation, which may explain why this receptor is expressed at the earliest stages of neurogenesis. Another signalling system which also exerts its influence on neurogenesis through active inhibition is Delta-Notch. We show in vitro that at high cell densities which impede neuronal production by FGF-1, lowering the levels of expression of the receptor Notch by antisense oligonucleotide results in a significant increase in neuronal production. Thus, stem cell differentiation appears to be dependent on the outcome of interactions between a number of signalling pathways, some which promote specific lineages and some which inhibit.
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PMID:Regulation of neural stem cell differentiation in the forebrain. 979 60

gp130 is a signal-transducing receptor component used in common by the interleukin-6 (IL-6) family of hematopoietic and neurotrophic cytokines, including IL-6, IL-11, leukemia-inhibitory factor, ciliary neurotrophic factor, oncostatin-M, and cardiotrophin-1. We have examined in this study a role of gp130 in the nervous system by analyzing developmental cell death of several neuronal populations and the differentiation of astrocytes in gp130-deficient mice. A significant reduction was observed in the number of sensory neurons in L5 dorsal root ganglia and motoneurons in the facial nucleus, the nucleus ambiguus, and the lumbar spinal cord in gp130 -/- mice on embryonic day 18.5. On the other hand, no significant neuronal loss was detectable on day 14.5, suggesting a physiological role of gp130 in supporting newly generated neurons during the late phase of development when naturally occurring cell death takes place. Moreover, expression of an astrocyte marker, GFAP, was severely reduced in the brain of gp130 -/- mice. Our data demonstrate that gp130 expression is essential for survival of subgroups of differentiated motor and sensory neurons and for the differentiation of major populations of astrocytes in vivo.
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PMID:Developmental requirement of gp130 signaling in neuronal survival and astrocyte differentiation. 1037 52

Signals of interleukin 6 (IL-6) are transduced by binding of IL-6 to its cell surface receptor (IL-6R) and subsequent association of the resultant IL-6/IL-6R complex with gp130, the signal transducing receptor component utilized in common by all the IL-6 family of cytokines. A soluble form of IL-6R (sIL-6R), which lacks transmembrane and cytoplasmic regions, retains the ability to bind IL-6 and signal through gp130. We show here that a fusion protein of sIL-6R and IL-6 without a polypeptide linker, termed FP6, induces differentiation of astrocytes from fetal mouse neuroepithelial cells as potently as a representative IL-6 family cytokine, leukaemia inhibitory factor (LIF). FP6 has a potential to activate a transcription factor, signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases, ERK1 and ERK2, in these cells as does LIF. FP6 activates a promoter of the gene for an astrocytic marker, glial fibrillary acidic protein (GFAP), in neuroepithelial cells. This activation is virtually abolished by ectopic expression of a dominant-negative form of STAT3, or by introducing a point mutation into the STAT3 response element located in the GFAP promoter. These results suggest that FP6 induces astrocyte differentiation from neuroepithelial cells through STAT3 activation and that FP6 could be of use as a substitute for natural IL-6 family cytokines.
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PMID:Directly linked soluble IL-6 receptor-IL-6 fusion protein induces astrocyte differentiation from neuroepithelial cells via activation of STAT3. 1124 5

Retroviral infection can induce transcriptional activation of genes flanking the sites of proviral integration in target cells. Because integration is essentially random, this phenomenon can be exploited for random mutagenesis of the genome, and analysis of integration sites in tumors may identify potential oncogenes. Here we have investigated this strategy in the context of astrocytoma progression. Neuroectodermal explants from astrocytoma-prone GFAP-v-src transgenic mice were infected with the ecotropic Moloney murine leukemia virus (Mo-MuLV). In situ hybridization and FACS analysis indicated that astrocytes from E12.5-13.5 embryos were highly susceptible to retroviral infection and expressed viral RNA and proteins both in vitro and in vivo. In average 80% of neuroectodermal cells were infected in vitro with 9-14 proviral integrations per cell. Virus mobility assays confirmed that Mo-MuLV remained transcriptionally active and replicating in neuroectodermal primary cultures even after 45 days of cultivation. Proviral insertion sites were investigated by inverse long-range PCR. Analysis of a limited number of provirus flanking sequences in clones originated from in vitro infected GFAP-v-src neuroectodermal cells identified loci of possible relevance to tumorigenesis. Therefore, the approach described here might be suitable for acceleration of tumorigenesis in preneoplastic astrocytes. We expect this method to be useful for identifying genes involved in astrocytoma development/progression in animal models.
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PMID:Insertional mutagenesis of preneoplastic astrocytes by Moloney murine leukemia virus. 1151 90

Many studies have explored the premature aging of accelerated senescence-prone (SAMP8) mice. However, the cause of premature aging in this strain remains unknown. We analyzed the expression of ecotropic, xenotropic, and polytropic murine leukemia viruses (MuLVs) in the brains of accelerated senescence-resistant (SAMR1) and SAMP8 mice. No ecotropic mRNA was detected in SAMR1 mice, and only Akv-type ecotropic MuLV mRNA was detected in SAMP8 mice. Restriction mapping of the full-length infectious E-MuLV genome from SAMP8 confirmed its identity as Akv. mRNAs corresponding to a prototypical polytropic MuLV and to an unusual xenotropic MuLV were detected at equal levels in SAMP8 and SAMR1 mice, but no infectious virus of either host range type was detected. In order to determine the cellular localization of Akv expression in SAMP8 mice, we used immunohistochemistry and electron microscopy to detect expression of the E-MuLV capsid gag (CAgag) gene in striatum, brainstem, hippocampus, and cerebellum of 12-month-old SAMR1 and SAMP8 mice. The CAgag antigen was seen in the neurons, oligodendroglia, and vascular endothelium of these brain regions of SAMP8 mice, but not in SAMR1 mice. To evaluate the correlation between activation of astrocytes and expression of Akv, we performed double-immunohistochemical staining for both glial fibrillary acidic protein (GFAP) and CAgag in SAMR1 and SAMP8 mice. Strong astrocytic activation and extensive vacuolation were observed around CAgag-positive neurons in SAMP8 mice, whereas in SAMR1 mice neither astrocytosis nor vacuolation were present. CAgag antigen was also localized in astrocytes of the hippocampus region of SAMP8 mice. Electron micrography showed that a number of vacuoles were found in the cytoplasm of MuLV-positive neurons and the extracellular space surrounding these neurons showed lytic changes. These results suggest that endogenous Akv provirus is expressed in neurons, astrocytes, vascular endothelium, and oligodendroglia in the brains of SAMP8 and that this virus could play an important role in the brain aging processes in this mouse strain.
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PMID:Analysis of the expression of endogenous murine leukemia viruses in the brains of senescence-accelerated mice (SAMP8) and the relationship between expression and brain histopathology. 1243 Jul 17


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