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Calretinin promoter for suicide gene expression in malignant mesothelioma.

To achieve specific and efficient expression of transfected suicide gene in malignant mesothelioma cells, we explored the 5-flanking region (2.2 kb) of the calretinin gene as a tumor-specific promoter. RT-PCR analysis demonstrated the expression of calretinin mRNA in two human malignant mesothelioma cell lines (H2052 and 211 H). A reporting vector containing the calretinin promoter (pCAL-LUC) exhibited relatively high luciferase activity in these cell lines. After transfecting an expression vector containing the calretinin promoter-bound thymidine kinase gene (pCAL-TK) into the cells, we examined their sensitivity to ganciclovir (GCV). In the mesothelioma cell lines, the pCAL-TK transfected cells became about 100 times more sensitive to GCV than the parental cells. The calretinin promoter seems to be a promising candidate as a specific and efficient promoter in malignant mesothelioma.

Antiviral Agents↗
PubMed2001

Effects of cholesterol and apolipoprotein E on retinal abnormalities in ApoE-deficient mice.

PURPOSE: To examine the pathologic changes in the retina of apolipoprotein E (apoE)-deficient mice fed a high-cholesterol diet. METHODS: ApoE-deficient mice (ApoE) were maintained on either regular mouse chow (ApoE-R) or a high-cholesterol diet (ApoE-C) for 25 weeks. Age-matched control C57BL/6J mice (C57) were also maintained on either regular mouse chow (C57-R) or a cholesterol-containing diet (C57-C). Retinal function was assessed by dark-adapted electroretinography (ERG). The eyes were embedded, sectioned, and analyzed by histologic and immunohistochemical methods, as well as by light and transmission electron microscopy. RESULTS: After the 25-week feeding period, ERG tracings of ApoE-C mice revealed significant increases of a- and b-wave implicit times when compared with the C57-R group of mice. In addition, there were reductions in oscillatory potential (OP) amplitudes in the ApoE-C group. However, a- and b-wave amplitudes appeared to be unchanged among the four groups of mice. Light microscopic examination of the retinas showed that compared with control C57-R mice, ApoE-C mice had significantly lower cell numbers in the inner and outer nuclear layers (85.1% +/- 4.6%, P < 0.05 and 81.4% +/- 3.7%, P < 0.01 of C57-R controls, respectively). Transmission electron microscopy of apoE-deficient mice revealed cells of the inner nuclear layer with condensation of nuclear chromatin and perinuclear vacuolization in focal areas. Bruch's membrane was also found to be thicker, and its elastic lamina appeared disorganized and discontinuous. Immunohistochemistry demonstrated diminished or no immunoreactivity for carbonic anhydrase II and calretinin in the retinal layers of apoE-deficient mice. CONCLUSIONS: Overall, there were increasing abnormalities of retinal function and cellular morphology among the four groups of mice in the order of C57-R < C57-C < ApoE-R < ApoE-C. These findings suggest that apoE and/or cholesterol play an important role in retinal function.

Animals↗
PubMed2001

Cation binding properties of calretinin, an EF-hand calcium-binding protein.

Calretinin (CR) is a neuronal EF-hand protein previously characterized as a calcium (micromolar affinity) binding protein. CR-containing neurons are spared in some neurodegenerative diseases, although it is as yet unconfirmed how CR plays an active role in this protection. Higher levels of some metal cations (e.g. copper and zinc) are associated with these diseases. At the same time, metals such as terbium (NMR and fluorescence) cadmium (NMR) and manganese (EPR) serve as useful calcium analogues in the study of EF-hand proteins. We survey the binding of the above-mentioned metal cations that might affect the structure and function of CR. Competitive 45Ca2+-overlay, competitive terbium fluorescence and intrinsic tryptophan fluorescence are used to detect the binding of metal cations to CR. Terbium and copper (half-maximal effect of 15 microM) bind to CR. Terbium has a similar or greater affinity for the calcium-binding sites of CR than calcium. Copper quenches the fluorescence of terbium-bound CR, and CR tryptophan residues and competes weakly for 45Ca2+-binding sites. Cadmium, magnesium, manganese and zinc bind less strongly (half-maximal effects above 0.1 mM). Therefore, only terbium appears to be a suitable analytical calcium analogue in further studies of CR. The principal conclusion of this work is that copper, in addition to calcium, might be a factor in the function of CR and a link between CR and neurodegenerative diseases.

Animals↗
PubMed2001

Glutamate receptors in the rod pathway of the mammalian retina.

Rod bipolar (RB) cells of the mammalian retina release glutamate in a graded, light-dependent fashion from 20 to 40 ribbon synapses (dyads). At the dyads, two classes of amacrine cells, the AI and AII cells, are the postsynaptic partners. We examined the glutamate receptors (GluRs) that are expressed by AI and AII cells using immunocytochemistry with specific antibodies against GluR subunits. Sections of macaque monkey and rabbit retina were examined by confocal microscopy. AII amacrine cells were selectively labeled for calretinin, and AI cells in rabbits were labeled for 5-HT uptake. Thus, double- and triple-labeling for these markers and GluR subunits was possible. Electron microscopy using postembedding immunocytochemistry and double-labeling was applied to show the synaptic expression of GluRs. We also studied the synaptic localization of the two postsynaptic density proteins PSD-95 and glutamate receptor-interacting protein (GRIP). We found that AII amacrine cells express the AMPA receptor subunits GluR2/3 and GluR4 at the RB cell dyads, and they are clustered together with PSD-95. In contrast, AI amacrine cells express the delta1/2 subunits that appear to be associated with kainate receptor subunits and to be clustered together with GRIP. The RB cell dyad is therefore a synapse that initiates two functionally and molecularly distinct pathways: a "through conducting" pathway based on AMPA receptors and a modulatory pathway mediated by a combination of delta1/2 subunits and kainate receptors.

Animals↗
PubMed2002

Inhibition of caspases prevents ototoxic and ongoing hair cell death.

Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.

Amino Acid Chloromethyl Ketones↗
PubMed2002

Cholinergic innervation and calretinin-immunoreactive neurones in the hippocampus during postnatal development of the rat brain.

Immunohistochemical study of the cholinergic innervation of the hippocampal calretinin-containing cells was conducted on 28 rat brains of postnatal ages: P0, P4, P7, P14, P21, P30 and P60. Sections with double immunostaining for vesicular acetylcholine transporter (VAChT; the marker of cholinergic cells, fibres and terminals) and calretinin were analysed using confocal laser-scanning microscope. Obtained data demonstrate that during development as well as in adult species calretinin-containing neurones in the rat hippocampus form sparse synaptic contact with VAChT-ir terminals. It seems probable that cholinergic innervation is not crucial for the functioning of CR-ir cells--probably they remain under the greater influence of a system other than the cholinergic system.

Acetylcholine↗
PubMed2002

[A case of primary malignant retroperitoneal mesothelioma needed to differentiate adrenal tumor].

Malignant mesothelioma is a neoplasm which tends to develop along serosal surfaces, such as the pleura and peritoneum. We report a rare case of malignant retroperitoneal mesothelioma in a 27-year-old woman. The patient was admitted with a chief compliant of intermittent high fever once a month, and left retroperitoneal tumor was detected by dynamic abdominal computed tomography. Since an adrenal tumor was suspected, laparoscopic tumor extirpation was performed. Immunohistochemically tumor cells were positive for calretinin and thrombomodulin, but negative for carcinoembryonic antigen (CEA) and Ber-Ep4. Based on these findings, primary malignant retroperitoneal mesothelioma was diagnosed.

Adrenal Gland Neoplasms↗
PubMed2002

Expression of p73 and Reelin in the developing human cortex.

Cajal-Retzius (CR) cells of the developing neocortex secrete Reelin (Reln), a glycoprotein involved in neuronal migration. CR cells selectively express p73, a p53 family member implicated in cell survival and apoptosis. Immunocytochemistry in prenatal human telencephalon reveals a complex sequence of migration waves of p73- and Reln-immunoreactive (IR) neurons into the cortical marginal zone (MZ). At early preplate stages, p73/Reln-IR cells arise in distinct sectors of the telencephalon, including cortical primordium and ganglionic eminences. After the appearance of the cortical plate, further p73/Reln-IR cells originate in the medial periolfactory forebrain. In addition, p73 marks a novel cell population that appears at the choroid-cortical junction or cortical hem before the emergence of the dorsal hippocampus. A pronounced mediolateral gradient in the density of p73/Reln-IR neurons in the neocortical MZ at 8 gestational weeks suggests that a subset of CR cells migrate tangentially from cortical hem and taenia tecta into neocortical territory. This hypothesis is supported by the absence of p73-transcripts in prospective neocortex of p73-/-mice at embryonic day 12 (E12), whereas they are present in cortical hem and taenia tecta. In the p73-/- preplate, Reln is faintly expressed in a calretinin-positive cell population, not present in this form in the E12 wild-type cortex. At P2, Reln-IR CR cells are undetectable in the p73-/- cortex, whereas Reln-expression in interneurons is unchanged. Our results point to a close association between p73 and Reln in CR cells of the developing neocortex, with a partial dissociation in early preplate and basal telencephalon, and to a p73-mediated role of the cortical hem in neocortical development.

Animals↗
PubMed2002

The retina of Spalax ehrenbergi: novel histologic features supportive of a modified photosensory role.

PURPOSE: The retina of the blind mole rat Spalax ehrenbergi was compared with other vertebrate photosensitive organs in an attempt to correlate its histologic organization with a presumptive nonvisual photoreceptor role. METHODS: The eyes of eight adult animals were analyzed by light and electron microscopy, using conventional staining and immunolabeling with antibodies against phototransduction proteins and calretinin. RESULTS: Rods accounted for most of the photoreceptor cells in the Spalax retina, although their morphology is dissimilar to that of sighted mammals, in that they contained only rudimentary outer segments. The latter showed strong rod-opsin and transducin immunoreactions. The phagosomes in the retinal pigmentary epithelium were also rod-opsin positive. Synapses were evident at the photoreceptor cells pedicles. Occasionally, several synaptic active sites were present, suggesting cone cell origin; however, cone-opsin was not immunodetected in the study samples. Synaptic ribbon fields, sometimes distant to the active sites, resembled those found in the vertebrate pineal. The other retinal layers were somewhat less organized than in sighted mammals. Some cells were displaced and the calretinin-positive inner plexiform layer had no sublayers. Calretinin immunolabeling was found in horizontal, amacrine, and ganglion cells. Folding of the retina produced rosette-like images similar to those reported before in the retina of nocturnal mammals and in the avian pineal gland. CONCLUSIONS: These data suggest that the retina of the mole rat has undergone evolutionary restructuring to a photoreceptive pineal-like organization. This supports the thesis that the photoreceptor cells of this unique organ have been reprogrammed during the subterranean adaptation of Spalax, from their original visual function to mediating photoperiodic regulation.

Animals↗
PubMed2002

A selective reduction in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia patients.

OBJECTIVES: To determine the relative densities of the GABAergic subpopulation defined by calcium-binding proteins and to further study the importance of changes in GABAergic interneurons on neuropathology in the hippocampus in schizophrenia cases. METHODS: The relative densities and neuronal body size of cells immunoreactive for the calcium-binding proteins parvalbumin and calretinin as well as the area size of the hippocampal sub-fields were determined from the hippocampal tissue sections taken from schizophrenic patients and well-matched control subjects (15 per group). RESULTS: No significant difference in the density of calretinin-immunoreactive neurons and the neuronal body size of calretinin-positive neurons was found between subject groups. Relative to normal controls, schizophrenic patients showed a significant and profound deficit in the relative densities of parvalbumin-immunoreactive neurons in all hippocampal sub-fields. These reductions were more apparent in male schizophrenic patients and were unrelated to antipsychotic drug treatment, age or duration of illness. CONCLUSION: The findings provide further evidence to support a profound and selective abnormality of a sub- population of GABAergic neurons in the hippocampus in schizophrenia cases, and are consistent with the etiological hypothesis of the neurodevelopment of schizophrenia.

Adult↗
PubMed2002

[Content of calretinin-immunoreactive epitheliocytes of the stomach in patients with chronic gastritis and peptic ulcer].

The article covers the information about 50 patients with gastric ulcer (GU) and 110 patients with duodenal ulcer (DU). 60 healthy persons and 70 patients with chronic helicobacter gastritis (CHG) formed comparative groups. Calretinin-immunoreactive epitheliocytes in antral region's gastric mucous membrane were reaved by clinical-endoscopic morphological and immunohistochemical investigations. It is shown that hyperplasia of calretinin-immunoreactive cells is in CHG cases. On the contrary, in DU and GU there is hypoplasia of calretinin-immunoreactive cells. Diametrically opposed data on quantitative description of focused endocrine cells in patients with CHG and peptic ulcer disease permitted to make a conclusion about the importance of calretinin-immunoreactive cells in peptic ulcer. The results of the investigation made it possible to give the prognostic appreciation of CHG course and its transformation into peptic ulcer disease.

Antibodies, Monoclonal↗
PubMed2002

Morphology of calretinin-immunoreactive neurons in the superficial layers of hamster superior colliculus after enucleation: lack of co-localization with GABA.

We recently reported on the distribution and effects of eye enucleation on the immunoreactivity of calretinin in the superficial layers of the hamster superior colliculus (SC). In the present study, we describe the types of labeled cells and compare this labeling to that of GABA, the major inhibitory neurotransmitter in the central nervous system. An almost complete depletion of calretinin-immunoreactive (IR) fibers in the superficial layers of the contralateral SC was found following unilateral enucleation. On the contralateral SC, many calretinin-IR cells were newly appeared. The majority of the newly-appeared cells had small- to medium-sized round, oval, or vertical fusiform cell bodies. Two-color immunofluorescence revealed that none of these newly-appeared cells were labeled with an antibody to GABA. The present results show that the calretinin-IR cells are unique in the superficial hamster SC when compared to most of the other brain areas, where many calretinin-IR cells are GABAergic interneurons.

Animals↗
PubMed2003

Caspase inhibitors promote vestibular hair cell survival and function after aminoglycoside treatment in vivo.

The sensory hair cells of the inner ear undergo apoptosis after acoustic trauma or aminoglycoside antibiotic treatment, causing permanent auditory and vestibular deficits in humans. Previous studies have demonstrated a role for caspase activation in hair cell death and ototoxic injury that can be reduced by concurrent treatment with caspase inhibitors in vitro. In this study, we examined the protective effects of caspase inhibition on hair cell death in vivo after systemic injections of aminoglycosides. In one series of experiments, chickens were implanted with osmotic pumps that administrated the pan-caspase inhibitor z-Val-Ala-Asp(Ome)-fluoromethylketone (zVAD) into inner ear fluids. One day after the surgery, the animals received a 5 d course of treatment with streptomycin, a vestibulotoxic aminoglycoside. Direct infusion of zVAD into the vestibule significantly increased hair cell survival after streptomycin treatment. A second series of experiments determined whether rescued hair cells could function as sensory receptors. Animals treated with streptomycin displayed vestibular system impairment as measured by a greatly reduced vestibulo-ocular response (VOR). In contrast, animals that received concurrent systemic administration of zVAD with streptomycin had both significantly greater hair cell survival and significantly increased VOR responses, as compared with animals treated with streptomycin alone. These findings suggest that inhibiting the activation of caspases promotes the survival of hair cells and protects against vestibular function deficits after aminoglycoside treatment.

Amino Acid Chloromethyl Ketones↗
PubMed2003

Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.

Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothesis, we evaluated the expression of mRNAs for PV, another calcium-binding protein, calretinin (CR), and glutamic acid decarboxylase (GAD67) in postmortem brain specimens from 15 pairs of subjects with schizophrenia and matched control subjects using single- and dual-label in situ hybridization. Signal intensity for PV mRNA expression in PFC area 9 was significantly decreased in the subjects with schizophrenia, predominantly in layers III and IV. Analysis at the cellular level revealed that this decrease was attributable principally to a reduction in PV mRNA expression per neuron rather than by a decreased density of PV mRNA-positive neurons. In contrast, the same measures of CR mRNA expression were not altered in schizophrenia. These findings were confirmed by findings from cDNA microarray studies using different probes. Across the subjects with schizophrenia, the decrease in neuronal PV mRNA expression was highly associated (r = 0.84) with the decrease in the density of neurons containing detectable levels of GAD67 mRNA. Furthermore, simultaneous detection of PV and GAD67 mRNAs revealed that in subjects with schizophrenia only 55% of PV mRNA-positive neurons had detectable levels of GAD67 mRNA. Given the critical role that PV-containing GABA neurons appear to play in regulating the cognitive functions mediated by the PFC, the selective alterations in gene expression in these neurons may contribute to the cognitive deficits characteristic of schizophrenia.

Adult↗
PubMed2003

Neurochemical heterogeneity of retinal bipolar cells.

BACKGROUND: Retinal bipolar cells show neurochemical changes in response to retinal insult, which could have profound effects on retinal function or recovery after insult however, the neurochemistry of bipolar cells is incompletely understood. METHODS The distribution of the amino acid neurotransmitters glutamate, gamma-aminobutyric acid (GABA), and glycine, and the metabolic amino acids, aspartate and glutamine, was examined immunocytochemically in the retina of the tiger salamander, a major model for the study of retinal anatomy and function. RESULTS: Each amino acid showed a unique distribution among retinal bipolar cells. All bipolar cells appear to contain glutamate and, under appropriate conditions, may also contain aspartate. GABA and glycine were restricted to a subset of conventionally placed bipolar cells located in the inner nuclear layer, but were not present in displaced bipolar cells located in the outer nuclear layer. In contrast, high levels of glutamine were almost exclusively restricted to displaced bipolar cells. Analysis of co-localization patterns revealed several different amino acid signatures within the bipolar cell population. CONCLUSIONS: The striking neurochemical heterogeneity among bipolar cells suggests important differences in signaling and metabolism that could affect cell survival, plasticity, and functional recovery from retinal insult in a cell-type-specific manner.

Ambystoma↗
PubMed2003

Abnormal dysbindin expression in cerebellar mossy fiber synapses in the mdx mouse model of Duchenne muscular dystrophy.

The dystrophin-associated protein complex (DPC), comprising sarcoglycans, dystroglycans, dystrobrevins, and syntrophins, is a component of synapses both in muscle and brain. Dysbindin is a novel component of the DPC, which binds to beta-dystrobrevin and may serve as an adaptor protein that links the DPC to an intracellular signaling cascade. Disruption of the DPC results in muscular dystrophy, and mutations in the human ortholog of dysbindin have been implicated in the pathogenesis of schizophrenia. In both cases, patients also present with neurological symptoms reminiscent of cerebellar problems. In the mouse cerebellum, dysbindin immunoreactivity is expressed at high levels in a subset of mossy fiber synaptic glomeruli in the granular layer. Lower levels of dysbindin immunoreactivity are also detected in Purkinje cell dendrites. In the cerebellar vermis, dysbindin-immunoreactive glomeruli are restricted to an array of parasagittal stripes that bears a consistent relationship to Purkinje cell parasagittal band boundaries as defined by the expression of the respiratory isoenzyme zebrin II/aldolase c. In a mouse model of Duchenne muscular dystrophy, the mdx mutant, in which dystrophin is not expressed, there is a dramatic increase in the number of dysbindin-immunoreactive glomeruli in the posterior cerebellar vermis. Moreover, the topography of the terminal fields is disrupted, replacing the stripes by a homogeneous distribution. Abnormal synaptic organization in the cerebellum may contribute to the neurological problems associated with muscular dystrophy and schizophrenia.

Animals↗
PubMed2003

Altered neuronal excitability in cerebellar granule cells of mice lacking calretinin.

Calcium-binding proteins such as calretinin are abundantly expressed in distinctive patterns in the CNS, but their physiological function remains poorly understood. Calretinin is expressed in cerebellar granule cells, which provide the major excitatory input to Purkinje cells through parallel fibers. Calretinin-deficient mice exhibit dramatic alterations in motor coordination and Purkinje cell firing recorded in vivo through unknown mechanisms. In the present study, we used patch-clamp recording techniques in acute slice preparation to investigate the effect of a null mutation of the calretinin gene on the intrinsic electroresponsiveness of cerebellar granule cells at a mature developmental stage. Calretinin-deficient granule cells exhibit faster action potentials and generate repetitive spike discharge showing an enhanced frequency increase with injected currents. These alterations disappear when 0.15 mm of the exogenous fast-calcium buffer BAPTA is infused in the cytosol to restore the calcium-buffering capacity. A proposed mathematical model demonstrates that the observed alterations of granule cell excitability can be explained by a decreased cytosolic calcium-buffering capacity resulting from the absence of calretinin. This result suggests that calcium-binding proteins modulate intrinsic neuronal excitability and may therefore play a role in information processing in the CNS.

Animals↗