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At least 325 records · Page 18Linked to original sources
PubMed1993

Reorganization of brain spectrin (fodrin) during differentiation of PC12 cells.

Fodrin has been shown to redistribute dynamically between cytoplasmic and plasma membrane-associated compartments upon the differentiation of T lymphocytes. We studied the changes of distribution of fodrin in PC12 cells upon neuronal differentiation induced by nerve growth factor. To visualize preferentially the elements that were tightly associated with cytoskeletal structures, we performed immunofluorescence and immunoelectron microscopy on saponin-extracted cells. In undifferentiated PC12 cells, fodrin was distributed mostly underneath the plasma membrane. However, after the administration of nerve growth factor, perinuclear spot-like aggregates of fodrin appeared. Double-labeling immunofluorescence revealed that the cytoplasmic fodrin spot was co-localized with the intermediate filament proteins, peripherin and neurofilament. Immunogold electron microscopy showed that fodrin and neurofilament were localized in close association in the perinuclear regions enriched with intermediate filaments. With prolonged exposure to nerve growth factor, fodrin and intermediate filaments spread to the cytoplasm and neurites. These results suggest that there is a dynamic reorganization of fodrin during differentiation of PC12 cells, and that fodrin is first recruited in the perinuclear region closely associated with intermediate filaments. This dynamic reorganization of fodrin may represent important, previously unrecognized aspects of the morphological differentiation of neurons.

Animals↗
PubMed1993

Rectospinal neurons: cell bodies, pathways, immunocytochemistry and ultrastructure.

A novel class of enteric neurons projecting directly from the rectal wall to the spinal cord, "rectospinal neurons", was investigated in rats by combined retrograde neuronal tracing, immunocytochemistry and electron microscopy. Rectospinal neurons were almost confined to myenteric ganglia of the distal rectum below the pelvic diaphragm and were labeled preferentially by injections into spinal cord segments L6/S1. Injections into more rostral spinal cord segments resulted in hardly any labeled enteric neurons. Dorsal and ventral rhizotomy experiments indicated an almost exclusive projection of rectospinal neurons through dorsal roots L6/S1 to the respective spinal cord segments. Among various peptides immunostained, vasoactive intestinal polypeptide and calcitonin gene-related peptide were selectively found in rectospinal neurons, which were also shown to contain calbindin, neurofilament protein- and peripherin-immunoreactivity. Vasoactive intestinal polypeptide- and calbindin-immunostaining were frequently co-localized in the same perikarya, while calcitonin gene-related peptide-immunoreactive rectospinal neurons probably represented a separate population. Neonatal capsaicin treatment did not significantly reduce the number of rectospinal neurons. Electron microscopy revealed synaptic contacts on the surface of rectospinal neurons. Taken together, these results establish rectospinal neurons as an anatomically and neurochemically distinct class of enteric neurons. Synaptic contacts on rectospinal neurons suggest that these neurons may function as a direct link from the enteric to the central nervous system, thus indicating that connections between these two networks are reciprocal.

Afferent Pathways↗
PubMed1991

Autosomal dominant retinitis pigmentosa: localization of a disease gene (RP6) to the short arm of chromosome 6.

DNA from members of an Irish pedigree presenting with late onset autosomal dominant retinitis pigmentosa (ADRP) have been typed with a series of genetic markers from chromosome 6p. Positive two-point lod scores have been obtained with five markers (D6S89: theta = 0.10, Z = 3.338; D6S109: theta = 0.10, Z = 3.932; D6S105: theta = 0.00, Z = 6.081; HLA-DRA: theta = 0.00, Z = 4.364; and RDS: theta = 0.00, Z = 5.376). In a series of overlapping multipoint analyses a lod score of 6.6 was obtained, maximizing at HLA-DRA and hence localizing the ADRP gene (RP5) segregating in this pedigree to 6p. These data provide direct evidence for an additional autosomal dominant RP locus and strongly implicate the human equivalent of the mouse retinal degeneration slow (rds) gene, peripherin-rds, as a candidate for autosomal dominant retinitis pigmentosa.

Base Sequence↗
PubMed1995

The cellular function of MASH1 in autonomic neurogenesis.

Using primary cultures and immortalized multipotential stem cell lines derived from wild-type and Mash1 mutant neural crest cells, we have analyzed the cellular function of MASH1 in autonomic neurogenesis. We present evidence for the existence of a precursor expressing MASH1 and neuronal markers such as neurofilament, neuron-specific tubulin, and tetanus toxin receptor. This cell has a nonneuronal morphology. Differentiation of this precursor to neurons that express markers such as SCG10, peripherin, and neuron-specific enolase is dependent upon MASH1 function. These data imply that the differentiation of autonomic neurons from uncommitted neural crest cells occurs in several sequential steps. Moreover, they suggest that MASH1 does not commit multipotent cells to a neural fate, like its Drosophila achaete-scute counterparts, but rather promotes the differentiation of a committed neuronal precursor.

Animals↗
PubMed2006

Delayed transactivation of the receptor for nerve growth factor is required for sustained signaling and differentiation by alpha2-adrenergic receptors in transfected PC12 cells.

Alpha2-adrenergic receptors have been reported to induce subtype-specific neuronal differentiation in vitro, but the signaling mechanisms that mediate this effect have not been characterized. In the present study we found that stimulated alpha2-ARs induce delayed transactivation of TrkA in PC12 cells. The transactivation of TrkA was sensitive to the PP1 inhibitor of the Src family kinases and required prior transactivation of the EGF receptor. Moreover, alpha2-adrenergic receptors induced sustained activation of MAPK and Akt. The sustained activation of Akt, but not of MAPK, was subtype-specific and correlated with the neuronal differentiation of PC12 cells, with the order alpha2A<alpha2B<alpha2C. Furthermore, stimulated alpha2-ARs induced an increased over time expression of the cell cycle associated proteins, p21WAF1 and Cyclin D1 and led to cell cycle arrest in a similar subtype-specific manner. Contrary to sustained activation of MAPK, the persistent activation of Akt and of p21WAF1 and Cyclin D1 as well as neurite outgrowth and expression of the neuronal marker peripherin, were all blocked by K252a an inhibitor of TrkA activity. Together these results demonstrate a novel outcome following alpha2-AR-mediated EGFR transactivation, being the consecutive transactivation of TrkA, and that this event may mediate the subtype-specific differentiation of alpha2-AR-expressing PC12 cells.

Animals↗
PubMed2005

Role of the peripheral benzodiazepine receptor in sensory neuron regeneration.

Peripheral benzodiazepine receptor (PBR) expression increases in small dorsal root ganglion (DRG) sensory neurons after peripheral nerve injury. To determine the functional significance of this induction, we evaluated the effects of PBR ligands on rodent sensory axon outgrowth. In vitro, Ro5-4864, a PBR agonist, enhanced outgrowth only of small peripherin-positive DRG neurons. When DRG cells were preconditioned into an active growth state by a prior peripheral nerve injury Ro5-4864 augmented and PK 11195, a PBR antagonist, blocked the injury-induced increased outgrowth. In vivo, Ro5-4864 increased the initiation of regeneration after a sciatic nerve crush injury and the number of GAP-43-positive axons in the distal nerve while PK 11195 inhibited the enhanced growth produced by a preconditioning lesion. These results show that PBR has a role in the early regenerative response of small caliber sensory axons, the preconditioning effect, and that PBR agonists enhance sensory axon regeneration.

Animals↗
PubMed2004

Expression and distribution of mu opioid receptors in the inner ear of the rat.

Opioid peptides have demonstrated modulatory effects on the vestibular afferent discharge and are putative vestibular efferent neuromodulators. The distribution of their receptors in the mammalian vestibular epithelia is not known. We used reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridization, Western blots and immunohistochemistry to study the expression of mu opioid receptor (MOR) in the Scarpa's ganglia and cristae ampullares of rats. MOR transcript was only detected in the somata of the vestibular afferent neurons. MOR-like immunoreactivity was observed in the somata of vestibular afferents and in nerve terminals in the cristae ampullares epithelia both in the center and peripheral regions. Double labeling of cristae sections with the MOR1 antibody in combination with antibodies against calretinin (a marker for vestibular afferents terminating in calices) and peripherin (a marker for afferents terminating in boutons), respectively showed that MOR1 immunoreactivity was in calyx, dimorphic and bouton vestibular afferents. MOR immunoreactivity was not detected in vestibular efferent fibers identified with choline acetyltransferase immunohistochemistry. These results indicate that MOR may mediate effects of vestibular efferents on afferents.

Animals↗
PubMed2005

Varicella zoster virus induces neuropathic changes in rat dorsal root ganglia and behavioral reflex sensitisation that is attenuated by gabapentin or sodium channel blocking drugs.

Reactivation of latent varicella zoster virus (VZV) within sensory trigeminal and dorsal root ganglia (DRG) neurons produces shingles (zoster), often accompanied by a chronic neuropathic pain state, post-herpetic neuralgia (PHN). PHN persists despite latency of the virus within human sensory ganglia and is often unresponsive to current analgesic or antiviral agents. To study the basis of varicella zoster-induced pain, we have utilised a recently developed model of chronic VZV infection in rodents. Immunohistochemical analysis of DRG following VZV infection showed the presence of a viral immediate early gene protein (IE62) co-expressed with markers of A- (neurofilament-200; NF-200) and C- (peripherin) afferent sensory neurons. There was increased expression of neuropeptide Y (NPY) in neurons co-expressing NF-200. In addition, there was an increased expression of alpha2delta1 calcium channel, Na(v)1.3 and Na(v)1.8 sodium channels, the neuropeptide galanin and the nerve injury marker, Activating Transcription Factor-3 (ATF-3) as determined by Western blotting in DRG of VZV-infected rats. VZV infection induced increased behavioral reflex responsiveness to both noxious thermal and mechanical stimuli ipsilateral to injection (lasting up to 10 weeks post-infection) that is mediated by spinal NMDA receptors. These changes were reversed by systemic administration of gabapentin or the sodium channel blockers, mexiletine and lamotrigine, but not by the non-steroidal anti-inflammatory agent, diclofenac. This is the first time that the profile of VZV infection-induced phenotypic changes in DRG has been shown in rodents and reveals that this profile appears to be broadly similar (but not identical) to changes in other neuropathic pain models.

Amines↗
PubMed2001

Morphological variation in the tyrosine receptor kinase A-immunoreactive periodontal ligament epithelium of developing and mature rats.

Tyrosine receptor kinase A (trkA) is the high-affinity receptor for nerve growth factor. It has been found in several non-neuronal cell types, indicating biological roles independent of neural function, as well as in the nervous system. An initial study demonstrated that an antibody to the full extracellular domain did not label periodontal ligament epithelium (PLE; also known as epithelial rests of Malassez), but that another antibody which recognises a truncated 41-kDa form of trkA did label PLE. Thus, truncated trkA-immunoreactive (-IR) PLE was further investigated here in developing molars of young rats, and in its mature form in adult rat molars, for its reaction to moderate or deep molar injuries, and for its appearance along the continuously erupting incisors of mature rats. In some of the adult rat molars we also analysed the association of nerve fibres with PLE using antibodies for p75 neurotrophin receptor or peripherin. Rat jaws were fixed with 4% formaldehyde and demineralised, and bound antibody was detected with avidin-biotin-peroxidase and diaminobenzidine or fluorescence procedures. Light microscopy showed great variation in the appearance of trkA-IR PLE and considerable morphological changes during the eruption of molars and incisors. By electron microscopy it was shown that trkA-IR was not uniformly distributed in PLE cells but rather was concentrated in the peripheral zones of each cell cluster. Tooth injury did not influence the form or occurrence of PLE unless there was specific destruction of a ligament region. Qualitative analyses of nerve fibres showed that they only rarely innervated PLE in adult rats, indicating that the truncated receptor has non-neuronal functions in this epithelium. These results suggest that neurotrophin growth factors, acting via truncated trkA receptors, affect the interactions between PLE cells and the periodontal ligament, with fewer PLE interactions with nerves. Furthermore, the expression of these receptors on PLE supports the possibility that these cells are active during tooth development and eruption rather than being merely passive remnants of the degenerating tooth sheath. The similar trkA-IR of PLE and junctional epithelium, as well as their structural association, suggests interactions between these two epithelia.

Animals↗
PubMed1997

Axonal cytoskeletal pathology in aged and diabetic human sympathetic autonomic ganglia.

Prevertebral sympathetic ganglia develop markedly enlarged argyrophilic neurites as a function of age, gender and diabetes. Immunolocalization studies demonstrate their preferential labeling with antisera to highly phosphorylated 200 kDa neurofilament (NF-H) epitopes, NPY, peripherin and synapsin I, but not to hypophosphorylated NF-M and NF-H or MAP-2. The immunophenotype of dystrophic neurites in conjunction with the results of histochemical and ultrastructural studies are consistent with the terminal axonal and/or synaptic origin of neuritic dystrophy in the sympathetic ganglia of aged and diabetic human subjects.

Adolescent↗
PubMed1998

Glial cells potentiate kainate-induced neuronal death in a motoneuron-enriched spinal coculture system.

AMPA/kainate receptor-mediated excitotoxicity is believed to play a pathogenic role in amyotrophic lateral sclerosis. To further characterize the mechanisms involved in AMPA/kainate receptor-mediated motoneuron injury, we investigated the influence of spinal glial cells on kainate-induced motoneuron death in vitro. A motoneuron-enriched neuronal population was obtained from embryonic mouse spinal cord by metrizamide density centrifugation. This population was cultured either on a pre-established glial feeder layer of ventral spinal origin (coculture) or in glia-free conditions (monoculture). Glial feeder layers significantly enhanced basal survival of neurons, and supported neuronal differentiation as judged by neuronal morphology and expression of the motoneuron markers peripherin and SMI-32. Neuronal vulnerability to kainate was two- to three-fold higher in coculture than in monoculture, and increased significantly with time in coculture. The effects of glial feeder layers on neuronal basal survival, differentiation and kainate vulnerability were not mimicked by conditioned medium from glial cells. The increase in neuronal kainate vulnerability with time in coculture was associated with a marked rise in the proportion of cocultured neurons possessing Ca2+-permeable AMPA/kainate receptors, as determined by kainate-activated Co2+-uptake. Neurons in monoculture were unstained by kainate-activated Co2+-uptake. Neurons were immunoreactive to specific antibodies against the AMPA receptor subunits GluR1 and GluR2 both in monoculture and coculture. This study indicates that motoneuron differentiation in coculture is associated with increased vulnerability to kainate and increased expression of Ca2+-permeable AMPA/kainate receptors. In this paradigm glial cells support basal survival and differentiation of neurons, but potentiate kainate-induced neuronal death.

Animals↗
PubMed1997

The mouse filensin gene: structure and evolutionary relation to other intermediate filament genes.

Filensin and phakinin are two lens-specific members of the intermediate filament (IF) superfamily of proteins. They coassemble to form a beaded submembraneous filamentous network, the beaded filaments (BFs). The low sequence homology and differences in assembly compared to other IF proteins do not allow their classification in any of the five IF subgroups. The organization of the phakinin gene exon/intron boundaries provides evidence that this partner may be sharing a common origin with type I cytokeratin genes. Here we report the molecular cloning, sequence and characterization of the mouse filensin gene. The filensin gene consists of 8 exons and 7 introns, with 6 introns interrupting its rod domain in a highly conserved manner characteristic of type III IF genes, like vimentin, desmin, or peripherin. Of the two tail domain exons the one adjacent to the rod domain, compares to exon 7 of the non-neuronal cytoplasmic IF gene of helix aspersa and to the lamin region bridging the end of the rod domain to the nuclear localization signal. Altogether, these observations indicate that the lens beaded filaments form an independent class of IF.

Amino Acid Sequence↗
PubMed1999

Targeted expression of an oncogenic adaptor protein v-Crk potentiates axonal growth in dorsal root ganglia and motor neurons in vivo.

The ability of neurons to survive and to target axonal growth requires a coordinated series of cell extrinsic and intrinsic events. Previously, in a cellular model for neuronal differentiation, we showed that pheochromocytoma (PC12) cells expressing v-Crk, an oncogenic form of the SH2/SH3-containing c-Crk adaptor protein, potentiates axonal growth and prolongs nerve growth factor (NGF)-independent survival. In the present study, we have generated transgenic mice that express v-Crk in sensory, motor, and enteric neurons by placing v-crk under the control of the neuron-specific peripherin promoter. In contrast to wild-type (wt) mice, dorsal root ganglia (DRG) neurons explanted from post-natal day 1 transgenic mice demonstrated a reduced dependence on trophic factors for both survival and axonogenesis. v-Crk also caused an increase in the number of surviving spinal motor neurons (SMN), and interestingly, upon staining of sternomastoid muscle fibers with rhodamine conjugated alpha-bungarotoxin, many muscle fibers displayed an apparent increase in volume of motor end plates, and an increase in complexity of neuromuscular junctions (NMJ). Our data suggest that v-Crk may be involved in transducing extracellular signals to regulate cytoskeletal organization, and may act on an intrinsic determinant for axonal growth in a variety of neural types including sensory and motor neurons during development.

Animals↗
PubMed2002

Cloning and characterization of the 5'-flanking region of the rat neuron-specific Class III beta-tubulin gene.

The promoter regions of several neuron-specific structural proteins (e.g. neurofilaments, peripherin, Talpha1-tubulin) have revealed potential regulatory elements that could contribute to the choice of a neuronal phenotype during development. We initiated study of the 5'-flanking region of the rat Class III neuron-specific beta-tubulin gene (betaIII-tubulin) because this gene is expressed at the time of terminal mitosis only in neurons and thus its promoter should be an excellent tool for studying neuron-specific gene expression during the transition from proliferative progenitor cell to early neuronal differentiation. We identified the minimal promoter region needed to drive expression of the betaIII-tubulin gene. This minimal region contains multiple putative binding sites for the transcription factors SP1 and AP2, as well as a central nervous system enhancer regulatory element and an E-box. A primer extension analysis identifies a single transcription start site. We highlight several putative regulatory elements that may modulate the expression of the betaIII-tubulin gene in a stage- and tissue-specific manner. In addition, we show that the first 490 bp of the promoter are sufficient to regulate betaIII-tubulin gene expression during neuronal differentiation of PCC7 cells.

5' Flanking Region↗
PubMed1991

Insulin-dependent diabetes mellitus.

Type I diabetes occurs as a result of T-cell-mediated beta-cell destruction. Several candidate antigens have been described recently, including glutamic acid decarboxylase, heat shock protein 65 and peripherin. Restricted T-cell receptor V beta gene usage in non-obese diabetic mice has been suggested but not yet proven. In addition to major histocompatibility genes, several non-H-2 predisposing genes have been mapped on chromosomes 1, 3 and 11.

Autoantigens↗
PubMed1997

Neurofilament and intermediate filament immunoreactivity in human intestinal myenteric neurons.

It has been reported previously that rat myenteric neurons have neurofilament (NF) immunoreactivity that differs from the brain. Now the result of a study of neurofilaments and intermediate filament immunoreactivity in human colon and ileum using a panel of antibodies and indirect immunofluorescence techniques is reported here. Results with polyclonal neurofilament antisera showed positive immunoreactivity in subsets of myenteric neurons. Results with peripherin and alpha-internexin showed immunoreactivity in some neurons that contained neurofilaments and in many that were neurofilament negative, similar to our observations in rat. Some monoclonal antibodies to epitopes on NF-M and NF-H demonstrated weak or negative immunoreactivity in human myenteric neurons yet showed positive immunoreactivity in brain. Some of these antibodies are phosphorylation dependent, suggesting NF-M and NF-H epitopes in myenteric neurons are not as phosphorylated as in brain; other antibodies are phosphorylation independent, suggesting other differences or masking of epitopes. In summary, neurofilaments are present in a subset of myenteric neurons. In those human myenteric neurons that contain them, the neurofilaments appear immunologically distinct from those in the brain.

Aged↗
PubMed1996

Intermediate filament aggregates in mitoses of primary cutaneous neuroendocrine (Merkel cell) carcinoma.

Primary cutaneous neuroendocrine carcinomas express different kinds of intermediate filaments and frequently in a 'paranuclear globular' pattern. We have observed the same pattern not only in interphase but also in mitotic cells, which are very frequent in these tumours. We report a quantitative and morphological study of eight primary cutaneous neuroendocrine carcinomas stained with different antibodies against cytokeratins (CAM 5.2 and anticytokeratin 20), neurofilaments (70 kDa and 200 kDa) and peripherin. We have found a predominance of CAM 5.2 expression in interphase cells and of neurofilament proteins in mitotic cells; 87.02% of the interphase cells were positive with CAM 5.2 whereas only 6.08% were positive for neurofilaments (P < 0.01); 35.41% of the mitotic cells were positive with CAM 5.2, whereas 50% were positive for neurofilaments (P < 0.01). A correlation between a globular pattern of intermediate filament proteins and prognosis has not been found. We describe for the first time the division of neoplastic cells with a globular pattern; the presence of intermediate filament proteins with a globular pattern in all mitotic stages; and the uneven distribution of this formation between the two daughter cells.

Aged↗
PubMed2001

ATP-gated ion channel P2X(3) is increased in human inflammatory bowel disease.

P2X(3) is a novel ATP-gated cation channel that is selectively expressed by small-diameter sensory neurones in rodents, and may play a role in nociception by binding ATP released from damaged or inflamed tissues. We have studied, for the first time, P2X(3) immunoreactivity in human inflammatory bowel disease, using Western blotting and immunohistochemistry. A major 66-kDa specific protein was found by Western blotting in all colon extracts. In the inflamed group there was a significant two-fold increase in the relative optical density of the 66-kDa band (21.2 +/- 3.1; n=8) compared to controls (11.4 +/- 3.7; n=8; P=0.009). In the control colon, P2X(3)-immunoreactive neurones were scattered throughout the myenteric and submucosal plexuses, with some neurones showing immunopositive axons/dendrites. The pattern of immunostaining was similar to the neuronal marker peripherin. In general, the intensity of the staining was greater in myenteric than submucosal neurones. The number of P2X(3)-immunoreactive neurones was significantly increased in the myenteric plexus of inflamed colon compared to controls (n=13; P=0.01). In humans, unlike rodents, P2X(3) is thus not restricted to sensory neurones. Increased P2X(3) in inflamed intestine suggests a potential role in dysmotility and pain, for which it represents a new therapeutic target.

Adenosine Triphosphate↗