[Do anesthetics impair brain development?].
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Anesthetics↗
Biomedical subjects
J Z Kiss
Publications and source records attributed to J Z Kiss.
Expression and localization of VEGF-C and VEGFR-3 in glioblastomas and haemangioblastomas.
Primary human brain tumours account for approximately 2% of all cancers. High levels of expression of vascular endothelial growth factor-A (VEGF-A), a potent angiogenic factor, are linked to poor prognosis. In contrast, the potential role in human brain tumour biology of newer VEGF family members, VEGF-C and VEGF-D, both of which are lymphangiogenic factors, is poorly understood. In the present study, the expression of all VEGFs (VEGF-A, -B, -C, and -D) and their receptors (VEGFR-1, -2, and -3) has been assessed in 39 primary human brain tumours. The well-established findings were confirmed with VEGF-A. Surprisingly, however, VEGF-C and VEGF-D, as well as VEGFR-3, were expressed in some tumour types such as haemangioblastomas and glioblastomas, despite their lack of lymphatic vessels. VEGF-C and VEGFR-3 transcripts were localized to the tumour palisade around necrotic areas in glioblastomas and were evenly distributed throughout haemangioblastomas. VEGF-C protein was localized by immunohistochemistry to the palisade layer in glioblastomas. More than 50% of VEGF-C-positive cells also expressed the intermediate-stage inflammatory macrophage marker CD163; however, a significant proportion of VEGF-C-positive cells were CD163-negative. These data demonstrate the presence of molecules, primarily described as regulators of lymphangiogenesis, in normal human brain and brain tumours that are devoid of lymphatics. Their localization in macrophages points to a role in tumour-associated inflammation.
Biomarkers, Tumor↗
Sequential activation of p75 and TrkB is involved in dendritic development of subventricular zone-derived neuronal progenitors in vitro.
Dendritic arbor development of subventricular zone-derived interneurons is a critical step in their integration into functional circuits of the postnatal olfactory bulb. However, the mechanism and molecular control of this process remain unknown. In this study, we have developed a culture model where dendritic development of purified subventricular zone cells proceeds under serum-free conditions in the absence of added growth factors and non-neural cells. We demonstrate that the large majority of these cells in culture express GABA and elaborate dendritic arbors with spine-like protrusions but they do not possess axons. These neurons expressed receptors for neurotrophins including p75, TrkB and TrkC but not TrkA. Application of exogenous neurotrophins, including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and nerve growth factor (NGF), to cultures stimulated dendritic growth and led to more complex dendritic arbors during the initial 3 days in culture. Our results suggest that these effects are independent of Trk receptors and mediated by the p75/ceramide signaling pathway. We also show that brain-derived neurotrophic factor is the only neurotrophin that is able to influence late-phase dendritic development via TrkB receptor activation. These results suggest that dendritic arbor development of subventricular zone-derived cells may be regulated by neurotrophins through the activation of p75 and the TrkB receptor signaling pathways in a sequentially defined temporal pattern.
Actins↗
Recovery of evoked potentials, metabolic activity and behavior in a mouse model of somatosensory cortex lesion: role of the neural cell adhesion molecule (NCAM).
Understanding the processes that underlie functional recovery after cortical injury is a major challenge for neurobiology and clinical neurology. The aim of the present study was to establish a mouse model of functional recovery that would facilitate the investigation of the molecular and cellular events involved in cortical dynamics. We show that a focal injury of approximately 0.5 mm of diameter and 1 mm depth made in the barrel cortex of adult mice induced a transitory deficit that could be characterized using somatosensory evoked potential (SEP), metabolic mapping and a behavioral test. SEP recordings of short latency responses using an epicranial multi-array system showed a decreased cortical activity in the peri-lesion regions 2 weeks after the injury and a partial recovery to normal pattern 6 weeks after the lesion. Delayed SEP signals over the motor cortex were not altered by the injury. Metabolic mapping with [14C]deoxyglucose uptake in the surround of the injury reproduced the time course of deficit and recovery. Finally, a deficit in vibrissae related performance in a gap-crossing test 1 week after injury was followed by a functional recovery in the following 2 weeks. We show in addition that the recovery process is deficient and significantly delayed in NCAM knockout mice lacking all isoforms of NCAM (neural cell adhesion molecule)and PSA-NCAM. These results support the hypothesis that impairment and recovery of functions after focal cortical lesion involves remodeling of intact circuits surrounding the lesion and that the NCAM molecule participate in this process. The model opens new possibilities for investigating the role of candidate molecules in functional recovery using genetically modified mice.
Animals↗
Local gamma-aminobutyric acid and glutamate circuit control of hypophyseotrophic corticotropin-releasing factor neuron activity in the paraventricular nucleus of the hypothalamus.
Paraventricular corticotropin-releasing factor (CRF) neurons play a pivotal role in regulating neuroendocrine responses to stress. The mechanisms by which synaptic inputs control the activity of these neurons are not well understood. The present study was undertaken to determine the role of the intrinsic gamma-aminobutyric acid (GABA)- and glutamatergic neural circuits of the hypothalamic paraventricular nucleus (PVN) in the control of CRF neural activity. We show that in organotypic cultures of the PVN, blockade of the intrinsic GABAergic neurotransmission by the GABAA receptor antagonist bicuculline resulted in a significant increase in CRF secretion. The bicuculline-induced CRF secretory activity was abolished by the coadministration of the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazoleprionic acid (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Electrical stimulation of the CRF cell division elicited glutamatergic extracellular field potentials that were dramatically enhanced by bicuculline and were suppressed by CNQX. These results show that the functional activity of CRF neurons in organotypic cultures of the PVN is under a tonic inhibitory influence of an intrinsic GABAergic circuit. Suppression of GABAergic transmission appears to have a permissive role for inducing an increased secretory activity of CRF neurons that is driven by an excitatory glutamatergic network via AMPA/kainate receptors.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
A role for the polysialic acid-neural cell adhesion molecule in PDGF-induced chemotaxis of oligodendrocyte precursor cells.
Directed migration of oligodendrocyte precursor cells (OPCs) is important for myelin formation and repair but the mechanisms of directional control are poorly understood. Here we have tested the role of polysialic acid-neural cell adhesion molecule (PSA-NCAM) in the directional migration of OPCs towards platelet-derived growth factor (PDGF). Using a Boyden microchemotaxis chamber and the Dunn direct viewing chamber, we show that in concentration gradients of PDGF, PSA-positive OPCs polarize and efficiently migrate towards the source of PDGF (chemotaxis). The loss or inactivation of the polysialic tail of NCAM leads to an altered pattern of OPC migration in response to PDGF gradients. Cells under these conditions, while being polarized and migrating, show no bias of displacement towards the source of PDGF and make random turns. By contrast, directed migration of OPCs towards basic fibroblast growth factor was not affected by the removal of PSA. Moreover, inactivation of PSA does not interfere with the random migration pattern of cells in uniform concentrations of PDGF (chemokinesis). These results suggest that PSA-NCAM is specifically involved in establishing the directionality of OPC migration in response to the concentration gradient of PDGF, but it is not essential for cell motility per se.
Animals↗
Oligodendrocyte progenitor migration in response to injury of glial monolayers requires the polysialic neural cell-adhesion molecule.
Injury to the nervous system results in reactive astrogliosis that is a critical determinant of neuronal regeneration. To analyze glial responses to mechanical injury and the role of the polysialic neural cell adhesion molecule (PSA-NCAM) in this process, we established primary glia cultures from newborn rat cerebral cortex. Scratching a confluent monolayer of primary glial cells resulted in two major events: rapid migration of oligodendrocyte progenitor-like (O-2A) cells into the wounded area and development of polarized morphology of type 1 astrocytes at the wound edge. Migrating O-2A progenitors had a bipolar morphology and exhibited A2B5 and O4 immunolabeling. Once these cells were established inside the wounded area, they lost A2B5 immunoreactivity and differentiated into glial fibrillary acidic protein-positive astrocytes. Migrating O-2A cells expressed PSA-NCAM, but type 1 astrocytes at the wound edge did not. Treatment of wounded cultures with Endo-N, which specifically removes PSA from the surface of cells, resulted in a significant decrease in O-2A cell migration into the wounded area and completely blocked the wound closure. Video time-lapse analysis showed that, in the presence of Endo-N, O-2A cells remained motile and migrated short distances but did not move away from the monolayer. These results demonstrate that O-2A progenitors contribute to reactive astrogliosis in culture and that PSA-NCAM is involved in this process by regulating cell migration.
Animals↗
Removal of PSA from NCAM affects the survival of magnocellular vasopressin- and oxytocin-producing neurons in organotypic cultures of the paraventricular nucleus.
The expression of the polysialic acid neural cell adhesion molecule (PSA-NCAM) in the hypothalamo-neurohypophyseal system has been correlated with morphofunctional plasticity. In this study, we investigated the role of PSA-NCAM in the survival of oxytocin (OT)- and vasopressin (VP)-producing magnocellular cells of this system. We used a recently developed organotypic slice culture model of the rat hypothalamic paraventricular nucleus (PVN) in which ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) are potent survival factors for magnocellular neurons. We demonstrate by means of confocal microscopy that cultured magnocellular VP and OT neurons express strong immunoreactivity for PSA-NCAM. Removal of PSA from NCAM by the enzyme Endo N leads to a significant loss of both VP and OT neurons in the presence of low concentrations of CNTF. Endo N treatment did not change cell survival in the presence of LIF. These results suggest that, in addition to its role in neuro-glial plasticity, PSA-NCAM might also influence the trophic factor responsiveness of hypothalamic VP and OT neurosecretory cells.
Animals↗
Progressive neuronal and motor dysfunction in mice overexpressing the serine protease inhibitor protease nexin-1 in postmitotic neurons.
Perturbation of the homeostasis between proteases and their inhibitors has been associated with lesion-induced or degenerative neuronal changes. Protease nexin-1 (PN-1), a secreted serine protease inhibitor, is constitutively expressed in distinct neuronal cell populations of the adult CNS. In an earlier study we showed that transgenic mice with ectopic or increased expression of PN-1 in postnatal neurons have altered synaptic transmission. Here these mice are used to examine the impact of an extracellular proteolytic imbalance on long-term neuronal function. These mice develop disturbances in motor behavior from 12 weeks on, with some of the histopathological changes described in early stages of human motor neuron disease, and neurogenic muscle atrophy in old age. In addition, sensorimotor integration, measured by epicranial multichannel recording of sensory evoked potentials, is impaired. Our results suggest that axonal dysfunction rather than cell death underlies these phenotypes. In particular, long projecting neurons, namely cortical layer V pyramidal and spinal motor neurons, show an age-dependent vulnerability to PN-1 overexpression. These mice can serve to study early stages of in vivo neuronal dysfunction not yet associated with cell loss.
Amyloid beta-Protein Precursor↗
Red-light-induced positive phototropism in Arabidopsis roots.
The interaction between light and gravity is critical in determining the final form of a plant. For example, the competing activities of gravitropism and phototropism can determine the final orientation of a stem or root. The results reported here indicate that, in addition to the previously described blue-light-dependent negative phototropic response in roots, roots of Arahidopsis thaliana (L.) Heynh. display a previously unknown red-light-dependent positive phototropic response. Both phototropic responses in roots are considerably weaker than the graviresponse, which often masks phototropic curvature. However, through the use of mutant strains with impaired gravitropism, we were able to identify a red-light-dependent positive phototropic response in Arabidopsis roots. The red-induced positive phototropic response is considerably weaker than the blue-light response and is barely detectable in plants with a normal gravitropic response.
Arabidopsis↗
The role of neural cell adhesion molecules in plasticity and repair.
Repair and functional recovery after brain injury critically depends on structural and functional plasticity of preserved neuronal networks. A striking feature of brain structures where tissue reorganization and plasticity occur is a strong expression of the polysialylated neural cell adhesion molecule (PSA-NCAM). An important role of this molecule in various aspects of neuronal and synaptic plasticity has been revealed by many studies. Recently, a new mechanism has been elucidated whereby PSA-NCAM may contribute to signalling mediated by the neurotrophic factor BDNF, thereby sensitizing neurons to this growth factor. This mechanism was shown to be important for activity-induced synaptic plasticity and for the survival and differentiation of cortical neurons. A cross-talk between these molecules may, thus, reveal a key factor for properties of structural plasticity and in particular could mediate the activity-dependent aspects of synaptic network remodeling. Animal models have been developed to assess the role of these molecules in functional recovery after lesions.
Animals↗
Phototropism in Arabidopsis roots is mediated by two sensory systems.
Phototropism has been well-characterized in stems and stem-like organs, but there have been relatively few studies of root phototropism. Our experiments suggest that there are two photosensory systems that elicit phototropic responses in roots of Arabidopsis thaliana: a previously identified blue-light photoreceptor system mediated by phototropin (=NPH1 protein) and a novel red-light-based mechanism. The phototropic responses in roots are much weaker than the graviresponse, which competes with and often masks the phototropic response. It was through the use of mutant plants with a weakened graviresponse that we were able to identify the activity of the red-light-dependent phototropic system. In addition, the red-light-based photoresponse in roots is even weaker compared to the blue-light response. Our results also suggest that phytochrome may be involved in mediating positive phototropism in roots.
Arabidopsis↗
PSA-NCAM modulates BDNF-dependent survival and differentiation of cortical neurons.
We show that the loss or inactivation of the polysialic acid (PSA) tail of neural cell adhesion molecule (NCAM) on rat cortical neurons in culture leads to reduced differentiation and survival. The mechanism by which this negative effect is mediated appears to involve the neuronal response to brain-derived neurotrophic factor (BDNF): (i) in the absence of PSA or in the presence of excess free PSA added to the culture medium, BDNF-induced cell signalling is reduced; (ii) the addition of exogenous BDNF to the medium reverses the effect of PSA loss or inactivation. These data suggest that PSA-NCAM, previously shown to modulate cell migration and plasticity, is needed for an adequate sensitivity of neurons to BDNF.
Animals↗
Contribution of the neural cell adhesion molecule to neuronal and synaptic plasticity.
The neural cell adhesion molecule (NCAM) and its polysialylated form PSA-NCAM contribute to many aspects of the development and plasticity of the central nervous system. This includes mechanisms of cell differentiation and migration, neurite outgrowth, establishment of specific patterns of synaptic connections, synaptic plasticity and long-term potentiation. How NCAM and PSA-NCAM contribute to regulate all these different mechanisms remains essentially unknown. Adhesive properties appear to be important, but recent studies also point to possible interactions between NCAM and PSA-NCAM with intracellular signalling cascades that are essential to biological functions. Some of these mechanisms are discussed and a hypothesis is proposed based on the existence of cross-talk between these molecules and signalling pathways mediated by growth factors.
Animals↗
Restoration of gravitropic sensitivity in starch-deficient mutants of Arabidopsis by hypergravity.
Despite the extensive study of plant gravitropism, there have been few experiments which have utilized hypergravity as a tool to investigate gravisensitivity in flowering plants. Previous studies have shown that starch-deficient mutants of Arabidopsis are less sensitive to gravity compared to the wild-type (WT). In this report, the question addressed was whether hypergravity could restore the sensitivity of starch-deficient mutants of Arabidopsis. The strains examined include a WT, a starchless mutant and a reduced-starch mutant. Vertical orientation studies with dark-grown seedlings indicate that increased centrifugal acceleration improves orientation relative to the acceleration vector for all strains, even the WT. For starchless roots, growth of seedlings under constant 5 g acceleration was required to restore orientation to the level of the WT at 1 g. In contrast, approximately 10 g was required to restore the orientation of the starchless mutant hypocotyls to a WT level at 1 g. Examination of plastid position in root cap columella cells of the starchless mutant revealed that the restoration of gravitropic sensitivity was correlated with the sedimentation of plastids toward the distal cell wall. Even in WT plants, hypergravity caused greater sedimentation of plastids and improved gravitropic capability. Collectively, these experiments support the hypothesis of a statolith-based system of gravity perception in plants. As far as is known, this is the first report to use hypergravity to study the mechanisms of gravitropism in Arabidopsis.
Arabidopsis↗
Brain-derived neurotrophic factor restores long-term potentiation in polysialic acid-neural cell adhesion molecule-deficient hippocampus.
The neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) contribute to long-term potentiation (LTP) in the CA1 hippocampus. Here we report that the deficient LTP found in slices prepared from NCAM knockout mice and in organotypic slice cultures treated with Endo-N, an enzyme that cleaves the PSA moiety of NCAM, can be rescued by brain-derived neurotrophic factor (BDNF). This effect is not reproduced by nerve growth factor, but can be obtained with high concentrations of NT4/5. The effect of BDNF cannot be accounted for by modifications of N-methyl-D-aspartate receptor-dependent responses or of high-frequency bursts. PSA-NCAM, however, could directly interact with BDNF. Exogenous application of PSA residues or recombinant PSA-NCAM also prevents LTP. Furthermore trkB phosphorylation, and thus BDNF signaling, is reduced in both NCAM knockout mice and Endo-N-treated slice cultures. These results suggest that one action of PSA-NCAM could be to sensitize pyramidal neurons to BDNF, thereby modulating activity-dependent synaptic plasticity.
Animals↗
Plastid position in Arabidopsis columella cells is similar in microgravity and on a random-positioning machine.
In order to study gravity effects on plant structure and function, it may become necessary to remove the g-stimulus. On Earth, various instruments such as clinostats have been used by biologists in an attempt to neutralize the effects of gravity. In this study, the position of amyloplasts was assayed in columella cells in the roots of Arabidopsis thaliana (L.) Heynh. seedlings grown in the following conditions: on Earth, on a two-dimensional clinostat at 1 rpm, on a three-dimensional clinostat (also called a random-positioning machine, or an RPM), and in space (true microgravity). In addition, the effects of these gravity treatments on columella cell area and plastid area also were measured. In terms of the parameters measured, only amyloplast position was affected by the gravity treatments. Plastid position was not significantly different between spaceflight and RPM conditions but was significantly different between spaceflight and the classical two-dimensional clinostat treatments. Flanking columella cells showed a greater susceptibility to changes in gravity compared to the central columella cells. In addition, columella cells of seedlings that were grown on the RPM did not exhibit deleterious effects in terms of their ultrastructure as has been reported previously for seedlings grown on a two-dimensional clinostat. This study supports the hypothesis that the RPM provides a useful simulation of weightlessness.
Arabidopsis↗
Mechanisms of the early phases of plant gravitropism.
Gravitropism is directed growth of a plant or plant organ in response to gravity and can be divided into the following temporal sequence: perception, transduction, and response. This article is a review of the research on the early events of gravitropism (i.e., phenomena associated with the perception and transduction phases). The two major hypotheses for graviperception are the protoplast-pressure and starch-statolith models. While most researchers support the concept of statoliths, there are suggestions that plants have multiple mechanisms of perception. Evidence supports the hypothesis that the actin cytoskeleton is involved in graviperception/transduction, but the details of these mechanisms remain elusive. A number of recent developments, such as increased use of the molecular genetic approach, magnetophoresis, and laser ablation, have facilitated research in graviperception and have allowed for refinement of the current models. In addition, the entire continuum of acceleration forces from hypo- to hyper-gravity have been useful in studying perception mechanisms. Future interdisciplinary molecular approaches and the availability of sophisticated laboratories on the International Space Station should help to develop new insights into mechanisms of gravitropism in plants.
Gravitation↗