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The origin of introns and their role (if any) in gene expression, in the evolution of the genome, and in the generation of new expressed sequences are issues that are understood poorly, if at all. Multigene families provide a favorable opportunity for examining the evolutionary history of introns because it is possible to identify changes in intron placement and content since the divergence of family members from a common ancestral sequence. Here we report the complete sequence of the gene encoding the 68-kilodalton (kDa) neurofilament protein; the gene is a member of the intermediate filament multigene family that diverged over 600 million years ago. Five other members of this family (desmin, vimentin, glial fibrillary acidic protein, and type I and type II keratins) are encoded by genes with six or more introns at homologous positions. To our surprise, the number and placement of introns in the 68-kDa neurofilament protein gene were completely anomalous, with only three introns, none of which corresponded in position to introns in any characterized intermediate filament gene. This finding was all the more unexpected because comparative amino acid sequence data suggest a closer relationship of the 68-kDa neurofilament protein to desmin, vimentin, and glial fibrillary acidic protein than between any of these three proteins and the keratins. It appears likely that an mRNA-mediated transposition event was involved in the evolution of the 68-kDa neurofilament protein gene and that subsequent events led to the acquisition of at least two of the three introns present in the contemporary sequence.
Mol Cell Biol 1986 May
PMID:Anomalous placement of introns in a member of the intermediate filament multigene family: an evolutionary conundrum. 378 73

We have extended our analysis of human tumors using antibodies specific for each of the five types of intermediate filaments to neuroblastoma, ganglioneuroblastoma, pheochromocytoma, ependymoblastoma, and alveolar soft part sarcoma. Tumor cells in the three cases of neuroblastoma, as well as in the single case of alveolar soft part sarcoma, did not react positively with sera directed against any of the five intermediate filament types. We suppose, therefore, that neuroblastoma at least may be derived from a cell type - possibly present in peripheral neurones - which in vivo has very few or no intermediate filaments. In ganglioneuroblastoma and in pheochromocytoma the tumor cells were positive when tested with antibodies directed against neurofilaments and negative with those directed against other intermediate filament types. The ependymoblastoma was positive when tested with antibodies directed against glial fibrillary acidic protein (GFA) and negative when tested with antibodies against other intermediate filament types. Use of antibodies to the different intermediate filament types appears to be a valid way in which to classify tumors, and so far the data presented here and elsewhere support the hypothesis that tumor cells retain the intermediate filament type typical of their cell of origin. Wider use of these sera would seem particularly useful in cases such as neuroblastoma, rhabdomyosarcoma or lymphoma where diagnosis is currently difficult using conventional histological stains.
Virchows Arch B Cell Pathol Incl Mol Pathol 1982 Aug
PMID:Various sympathetic derived human tumors differ in neurofilament expression. Use in diagnosis of neuroblastoma, ganglioneuroblastoma and pheochromocytoma. 612 32

Survival of newborn mouse cerebellar Purkinje cells in dissociated monolayer cultures was substantially enhanced when the dissociated cells were plated on a substrate containing antibody to the Purkinje cell surface antigen Thy-1. Cells were identified by size, asymmetric arbors, uptake of gamma-aminobutyric acid (GABA), and failure to express glial fibrillary acidic protein. This selective enhancement was specific for antibody to the Thy-1.2 allele.
Cell Mol Neurobiol 1984 Sep
PMID:Enhanced survival of cultured cerebellar Purkinje cells by plating on antibody to Thy-1. 639 56

Stargazer mutant mice inherit a recessive neuronal excitability phenotype featuring frequent non-convulsive spike-wave seizures that arise from synchronous bursting in neocortical, thalamic and hippocampal networks. Immunocytochemistry reveals that granule cells in the mutant dentate gyrus aberrantly express neuropeptide Y (NPY) at multiple ages following the developmental onset of seizures. The ectopic NPY is selectively concentrated in the mossy fibers, co-localizing with the releasable dense core vesicle pool. The NPY content of native NPY+local circuit neurons is also elevated in the mutant CNS. There is no concurrent elevation of hippocampal 72 kDa heat shock protein (HSP72), glial fibrillary acidic protein (GFAP) or NADPH-diaphorase, three markers that are induced during cellular injury, and no evidence of granule cell loss. Since mossy fiber NPY expression appears after the developmental onset of spike-wave discharges and can be induced in wild type granule cells by electrical stimulation, the altered peptide phenotype is likely to reflect transynaptic gene induction triggered by synchronous bursting. These results link a specific pattern of repetitive synaptic input with selective molecular plasticity in dentate granule cells that may contribute to dynamic modifications in hippocampal network excitability.
Brain Res Mol Brain Res 1995 Jul
PMID:Aberrant expression of neuropeptide Y in hippocampal mossy fibers in the absence of local cell injury following the onset of spike-wave synchronization. 747 19

In the gracile axonal dystrophy (GAD) mutant mouse, the dying-back type axonal dystrophy of the primary afferent neurons in the gracile tract of the spinal cord was marked by severe gliosis characterized by the hypertrophy and proliferation of the fibrous astrocytes. Immunocytochemical observation for substance P (SP) revealed that SP-positive cells increased in the lesioned sites, primarily in the gracile nucleus of the medulla and subsequently in the gracile fasciculus of the spinal cord. The combined immunostaining of both SP and glial fibrillary acidic protein (GFAP) indicated that a strong correspondence exists between GFAP-positive networks and SP-positive grains, suggesting that SP was accumulated in the cytoplasm of astrocytes. The networks of SP-positive astrocytes spread all over the gracile tract and were densest at the subpial membrane. Similar lesions and SP activity were detected along the marginal zone of the lateral and ventral funiculi. Using an electron microscope, in addition to SP-positive axonal terminals in the gracile nucleus, most SP-positive cells in the gracile tract were identified as reactive astrocytes whose processes surrounded myelinated and nonmyelinated axons, and extended their foot processes to the blood vessels. By in situ hybridization histochemistry of SP mRNA, we confirmed the synthesis of SP in the astrocytes. Although the functional significance of SP within astrocytes is not established here, these results imply that the astrocytes may play a role as a gliotransmitter through which the progress of axonal degeneration in the spinal cord was modified.
Mol Chem Neuropathol 1993 Sep
PMID:Substance P-immunoreactive astrocytes in gracile sensory nervous tract of spinal cord in gracile axonal dystrophy mutant mouse. 750 92

There is a pressing need for a more accurate system of classifying human astrocytomas, one that is based on morphologic characteristics and that could also make use of distinctive biochemical markers. However, little is known about the phenotypic characteristics of astrocytomas. Recent studies have shown that the expression of proteins comprising the intermediate filament (IF) cytoskeleton of astrocytic cells is developmentally regulated. It is our hypothesis that this changing protein profile can be used as the basis of a system for clearly and objectively classifying astrocytomas. A spectrum of human astrocytomas has been examined by immunofluorescence microscopy employing antibodies to several IF structural subunit proteins (GFAP, vimentin, and keratins) and an IF-associated protein, IFAP-300kDa. These proteins occupy unique temporal niches in the cytogenesis of the astrocytic cells: keratins in cells of the neuroectoderm; vimentin and IFAP-300kDa in radial glia and immature glia; GFAP in mature astrocytes; and vimentin in some mature astrocytes. In agreement with previous reports, our immunofluorescence studies have revealed both GFAP and vimentin in all astrocytoma specimens. Two new observations, however, are of particular interest: IFAP-300kDa is detectable in all astrocytic tumors, and the proportion of keratin-containing cells present in the astrocytomas is in direct relationship to the degree of the malignancy. Because IFAP-300kDa is not present in either normal mature or reactive astrocytes, this protein appears to represent a specific marker of transformed (malignant) astrocytes. If it is presumed that higher malignancy grades represent the most dedifferentiated cellular state of the astrocytes, the presence of keratin-containing cells is not totally unexpected, given the ectodermal (epithelial) origin of the CNS. Specific developmentally regulated proteins of the IF cytoskeleton thus appear to hold great potential as diagnostic markers of astrocytomas and as tools for investigating the biology of these tumors.
Mol Chem Neuropathol
PMID:Proteins of the intermediate filament cytoskeleton as markers for astrocytes and human astrocytomas. 752 6

To assess the distribution of insulin-like growth-factor-related proteins during autoimmune CNS demyelination and remyelination, experimental autoimmune encephalomyelitis was produced by injecting Lewis rats with an emulsion containing guinea pig spinal cord and complete Freund's adjuvant. Tail weakness appeared at 10-12 days and was followed by hind and forelimb weakness. Paraplegia and incontinence were observed in some animals. From 8-40 days postinoculation (dpi), spinal cord sections were used to correlate lesion location and severity with mRNA distributions of insulin-like growth factor I (IGF-I), IGF-binding protein 2 (IGFBP-2), IGF-I-receptor (IGFR-I), glial fibrillary acidic protein (GFAP), and myelin basic protein (MBP). These were determined semiquantitatively by in situ hybridization. Fourteen dpi, there were inflammatory infiltrates and demyelination in both white matter (WM) and grey matter (GM). IGF-I and GFAP mRNAs were increased in these lesions and transcripts encoding myelin basic protein (MBP) were greatly reduced. Large lesions with extensive demyelination were evident in both WM and GM when mRNA levels of GFAP and IGF-I peaked 26 dpi. MBP mRNA levels began increasing 21 dpi and peaked 26 dpi, when a few thin regenerating myelin sheaths were found morphologically. Astrocytes, identified by their morphology and GFAP immunoreactivity, expressed very low levels of IGFBP-2 mRNA and peptide in normal controls; their levels were significantly higher 14 dpi, peaked 26 dpi, and then gradually decreased. Some neurons, as well as oligodendroglia in areas undergoing remyelination, expressed IGFR-I. Although levels of IGF-I, IGFBP-2, and GFAP mRNAs were highest in lesion areas, levels were also elevated around lesions and in some normal-appearing areas of WM and GM 14-40 dpi. The gene expression of both IGF-I and IGFBP-2 by hypertrophic GFAP-positive astrocytes was demonstrated 14-40 dpi by combined in situ hybridization and immunocytochemistry as well as by double immunostaining. Coexpression of IGF-I and IGFBP-2 in the same astrocyte was a frequent finding. Relative increases in both IGF-I, GFAP, IGFBP-2, IGFR-I, and MBP mRNAs peaked at about the same time. This suggests that during lesion progression and recovery, astrocytic expression of IGF-I-related peptides may reduce immune-mediated myelin injury. We also suggest that astrocytic IGFBP-2 in lesions may help target IGF-I to IGFR-I-expressing oligodendrocytes and promote remyelination of demyelinated axons.
Mol Cell Neurosci 1994 Oct
PMID:Astrocytes express insulin-like growth factor-I (IGF-I) and its binding protein, IGFBP-2, during demyelination induced by experimental autoimmune encephalomyelitis. 752 31

In situ hybridization was used to study the effect of IL-1 beta on acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF) mRNA expression in rat brain. Intraventricular injection of recombinant human IL-1 beta did not affect hybridization to aFGF mRNA but did induce significant and widespread increases in hybridization to bFGF mRNA. IL-1 beta induced increases in bFGF mRNA were bilaterally distributed and appeared to correspond with the distribution of non-neuronal cells. Thus, hybridization was increased in regions of both gray and white matter (e.g., corpus callosum), the ependymal lining of the third ventricle, and the pia matter. In hippocampus of IL-1 beta injected rats, hybridization was markedly increased in the molecular layers but not significantly increased in the neuronal cell layers. Elevations in bFGF mRNA were transient, peaking at 8 h postinjection in most areas. To determine if IL-1 beta effects were independent of activation of the hypothalamo-pituitary-adrenal axis, and to compare the cellular localization of increases in bFGF mRNA expression induced by IL-1 beta and bFGF, the regulation of bFGF expression was also studied in organotypic hippocampal slice cultures. Treatment of cultures with either IL-1 beta or bFGF stimulated the same general distribution of increases in bFGF mRNA as seen after IL-1 beta treatment in vivo with an additional effect on immature neurons within the hilar side of stratum granulosum; hybridization of bFGF mRNA was not increased in association with the more mature neurons of stratum pyramidale or stratum granulosum. Colocalization of bFGF cRNA hybridization with immunostaining for glial fibrillary acidic protein demonstrated that increases in bFGF mRNA induced both by IL-1 beta in vivo and in vitro and by bFGF in vitro were largely associated with astroglial cells. These findings suggest that IL-1 beta induction of bFGF contributes to the coactivation of these substances following various forms of insult to the CNS and initiates a cascade of trophic interactions that regulates processes of glial proliferation, neurotrophic factor expression, and neuroprotection.
Brain Res Mol Brain Res 1994 Nov
PMID:Interleukin-1 beta increases basic fibroblast growth factor mRNA expression in adult rat brain and organotypic hippocampal cultures. 753 32

Injection of colchicine, a mitogen inhibitor, in the dorsal third ventricle induced the expression of the growth associated protein-43 (GAP-43) mRNA in some groups of cells of the adult rat brain. These mRNAs were detected by in situ hybridization histochemistry using an alkaline phosphatase labeled oligonucleotide probe. A substantial up-regulation of GAP-43 mRNA was noticed by the increase of both the number of positive cells and the intensity of the hybridization signal. These changes were observed in the hypothalamic nuclei located near the ventral third ventricle, namely the preoptic area, the supraoptic nucleus, the peri- and the paraventricular nuclei of the hypothalamus, the dorsal subnucleus of the ventromedial nucleus, the arcuate nucleus and the posterior part of the peri-mammillary region. Such abundant GAP-43 mRNA positive cells have not been observed in control adult rat hypothalamus. Since the positive cell number and shape initially suggested that these were neurons or astrocytes, double labeling in situ hybridization using both radioactive (for the detection of GFAP mRNA as a marker of astrocyte) and non-radioactive (for the detection of GAP-43 mRNA) probes was carried out. This demonstrated that these GAP-43 mRNA positive cells were not astrocytes. In addition enhanced GAP-43 mRNA expression was also found in some neuronal component, particularly in neurosecretory magnocells of the pareaventricular and the supraoptic nuclei. This up-regulation was further confirmed by the Northern blot analysis. About five fold increase in GAP-43 mRNA in the colchicine-treated hypothalamic tissue was shown.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1995 Jun
PMID:Colchicine induces the GAP-43 gene expression in rat hypothalamus. 763 88

Pluripotent embryonic stem (ES) cell cultures provide an efficient method for genome manipulation with many applications in marine biotechnology. To develop this technology we have been working to derive fish ES cell lines for in vitro studies of embryo cell growth and differentiation and for the generation of transgenic fish. Zebrafish embryonal cell cultures were derived from blastula-stage embryos in LDF medium supplemented with fetal bovine serum, trout serum, trout embryo extract, selenium, insulin, and leukemia inhibitory factor. Cultures derived under these conditions on feeder layers of zebrafish embryonic fibroblasts possessed a diploid karyotype and exhibited an ES-like morphology with elevated levels of alkaline phosphatase enzyme activity. Injection of primary cell cultures derived from embryos of transgenic fish carrying neo produced chimeric fish detected by polymerase chain reaction analysis. Embryo cells cultured on poly-D-lysine substrate in the presence of retinoic acid or Buffalo rat liver cell-conditioned medium (BRL-CM) and a reduced serum concentration differentiated into neuronal cell types exhibiting elevated levels of acetylcholinesterase enzyme activity and expression of neurofilament and glial fibrillary acidic protein.
Mol Mar Biol Biotechnol 1995 Sep
PMID:ES-like cell cultures derived from early zebrafish embryos. 767 May 94


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