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1.
Int J Mol Sci ; 21(23)2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33255323

RESUMO

The translation of new therapies for spinal cord injury to clinical trials can be facilitated with large animal models close in morpho-physiological scale to humans. Here, we report functional restoration and morphological reorganization after spinal contusion in pigs, following a combined treatment of locomotor training facilitated with epidural electrical stimulation (EES) and cell-mediated triple gene therapy with umbilical cord blood mononuclear cells overexpressing recombinant vascular endothelial growth factor, glial-derived neurotrophic factor, and neural cell adhesion molecule. Preliminary results obtained on a small sample of pigs 2 months after spinal contusion revealed the difference in post-traumatic spinal cord outcomes in control and treated animals. In treated pigs, motor performance was enabled by EES and the corresponding morpho-functional changes in hind limb skeletal muscles were accompanied by the reorganization of the glial cell, the reaction of stress cell, and synaptic proteins. Our data demonstrate effects of combined EES-facilitated motor training and cell-mediated triple gene therapy after spinal contusion in large animals, informing a background for further animal studies and clinical translation.


Assuntos
Terapia por Estimulação Elétrica , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Moléculas de Adesão de Célula Nervosa/genética , Traumatismos da Medula Espinal/terapia , Fator A de Crescimento do Endotélio Vascular/genética , Adenoviridae/genética , Animais , Terapia Baseada em Transplante de Células e Tecidos/métodos , Modelos Animais de Doenças , Espaço Epidural , Terapia Genética/métodos , Vetores Genéticos/uso terapêutico , Fator Neurotrófico Derivado de Linhagem de Célula Glial/uso terapêutico , Humanos , Atividade Motora/genética , Atividade Motora/fisiologia , Moléculas de Adesão de Célula Nervosa/uso terapêutico , Neuroglia/transplante , Recuperação de Função Fisiológica/genética , Recuperação de Função Fisiológica/efeitos da radiação , Medula Espinal/fisiopatologia , Medula Espinal/efeitos da radiação , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/fisiopatologia , Suínos/genética , Fator A de Crescimento do Endotélio Vascular/uso terapêutico
2.
Cereb Cortex ; 30(4): 2358-2371, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-31812984

RESUMO

2p16.3 deletions, involving heterozygous NEUREXIN1 (NRXN1) deletion, dramatically increase the risk of developing neurodevelopmental disorders, including autism and schizophrenia. We have little understanding of how NRXN1 heterozygosity increases the risk of developing these disorders, particularly in terms of the impact on brain and neurotransmitter system function and brain network connectivity. Thus, here we characterize cerebral metabolism and functional brain network connectivity in Nrxn1α heterozygous mice (Nrxn1α+/- mice), and assess the impact of ketamine and dextro-amphetamine on cerebral metabolism in these animals. We show that heterozygous Nrxn1α deletion alters cerebral metabolism in neural systems implicated in autism and schizophrenia including the thalamus, mesolimbic system, and select cortical regions. Nrxn1α heterozygosity also reduces the efficiency of functional brain networks, through lost thalamic "rich club" and prefrontal cortex (PFC) hub connectivity and through reduced thalamic-PFC and thalamic "rich club" regional interconnectivity. Subanesthetic ketamine administration normalizes the thalamic hypermetabolism and partially normalizes thalamic disconnectivity present in Nrxn1α+/- mice, while cerebral metabolic responses to dextro-amphetamine are unaltered. The data provide new insight into the systems-level impact of heterozygous Nrxn1α deletion and how this increases the risk of developing neurodevelopmental disorders. The data also suggest that the thalamic dysfunction induced by heterozygous Nrxn1α deletion may be NMDA receptor-dependent.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Ketamina/administração & dosagem , Moléculas de Adesão de Célula Nervosa/genética , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/genética , Córtex Pré-Frontal/diagnóstico por imagem , Tálamo/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Deleção de Genes , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/efeitos dos fármacos , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Tálamo/efeitos dos fármacos
3.
Elife ; 72018 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-29424692

RESUMO

It has long been thought that the mammalian visual system is organized into parallel pathways, with incoming visual signals being parsed in the retina based on feature (e.g. color, contrast and motion) and then transmitted to the brain in unmixed, feature-specific channels. To faithfully convey feature-specific information from retina to cortex, thalamic relay cells must receive inputs from only a small number of functionally similar retinal ganglion cells. However, recent studies challenged this by revealing substantial levels of retinal convergence onto relay cells. Here, we sought to identify mechanisms responsible for the assembly of such convergence. Using an unbiased transcriptomics approach and targeted mutant mice, we discovered a critical role for the synaptic adhesion molecule Leucine Rich Repeat Transmembrane Neuronal 1 (LRRTM1) in the emergence of retinothalamic convergence. Importantly, LRRTM1 mutant mice display impairment in visual behaviors, suggesting a functional role of retinothalamic convergence in vision.


Assuntos
Moléculas de Adesão de Célula Nervosa/metabolismo , Retina/anatomia & histologia , Retina/fisiologia , Tálamo/anatomia & histologia , Tálamo/fisiologia , Vias Visuais/anatomia & histologia , Vias Visuais/fisiologia , Animais , Perfilação da Expressão Gênica , Proteínas de Membrana , Camundongos , Proteínas do Tecido Nervoso , Moléculas de Adesão de Célula Nervosa/genética , Células Ganglionares da Retina/fisiologia
4.
J Ethnopharmacol ; 214: 13-21, 2018 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-29217494

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoyao San (XYS) is a classic Chinese herbal formula for treatment of depression. The present study aimed to investigate the antidepressant effects of XYS in a rat model of chronic unpredictable mild stress (CUMS) and the underlying mechanisms. MATERIALS AND METHODS: A CUMS rat model of depression was established via 4 weeks of unpredictable stimulation. Then the rats were orally administered paroxetine and XYS for 2 weeks with continued stress. Behavioral assessments, including an open field test (OFT), sucrose preference test (SPT) and forced swim test (FST), were conducted to evaluate the antidepressant effects of XYS. The concentrations in rat plasma of tryptophan (Trp) and its metabolic products, including kynurenine (Kyn) and quinolinic acid (QUIN), were determined using high performance liquid chromatography tandem mass spectrometry with electrochemical detection (HPLC-MS/MS). The mRNA and protein levels in rat hippocampus of depression-related brain derived neurotrophic factor (BDNF), cyclic AMP response element binding protein (CREB) and nerve cell adhesion molecule (NCAM) were determined by real-time qPCR and Western blot, respectively. Enzyme Linked Immunosorbent Assay (ELISA) was used to detect the activities of indoleamine 2,3-dioxygenase (IDO) and kynurenine-3-monooxygenase (KMO) in rat plasma. RESULTS: The results showed that a successful CUMS rat model was established through 4 weeks of continuous unpredictable stimulation, as indicated by the significant decrease in locomotor activity and increase in immobility time in the OFT, reduction in body weight and food intake etc. Compared with the normal group, the concentrations of Kyn and QUIN had significantly (p < 0.05) decreased at day 28 in the control group, but then improved after drug treatment with paroxetine and XYS. There were no obvious changes in the activities of IDO and KMO. Compared with the normal group, the mRNA of NCAM, CREB and BDNF were significantly down-regulated (p < 0.001) in the control group, BDNF gene was up-regulated by paroxetine or XYS treatment, NCAM and CREB gene did not change in XYS group, protein expressions of BDNF and CREB were significantly increased, and NCAM was significantly reduced (p < 0.05). CONCLUSIONS: XYS reversed the abnormalities of the tryptophan-kynurenine metabolic pathways in depressed rats and achieved an excellent antidepressant effect. Its direct impact may be observed as changes in biological indicators in rat hippocampus tissue.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Hipocampo/efeitos dos fármacos , Cinurenina/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/metabolismo , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/sangue , Quinurenina 3-Mono-Oxigenase/genética , Quinurenina 3-Mono-Oxigenase/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Moléculas de Adesão de Célula Nervosa/genética , Moléculas de Adesão de Célula Nervosa/metabolismo , Ácido Quinolínico/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Triptofano/metabolismo
5.
Oncogene ; 31(5): 595-610, 2012 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-21706053

RESUMO

Semaphorins are implicated in glioma progression, although little is known about the underlying mechanisms. We have reported plexin-B3 expression in human gliomas, which upon stimulation by Sema5A causes significant inhibition of cell migration and invasion. The concomitant inactivation of Rac1 is of mechanistic importance because forced expression of constitutively active Rac1 abolishes these inhibitory effects. Furthermore, Sema5A induces prominent cell collapse and ramification of processes reminiscent of astrocytic morphology, which temporally associate with extensive disassembly of actin stress fibers and disruption of focal adhesions, followed by accumulation of actin patches in protrusions. Mechanistically, Sema5A induces transient protein kinase C (PKC) phosphorylation of fascin-1, which can reduce its actin-binding/bundling activities and temporally parallels its translocation from cell body to extending processes. PKC inhibition or fascin-1 knockdown is sufficient to abrogate Sema5A-induced morphological differentiation, whereas the process is hastened by forced expression of fascin-1. Intriguingly, Sema5A induces re-expression of glial fibrillary acidic protein (GFAP), which when silenced restricts differentiation of glioma cells to bipolar instead of multipolar morphology. Therefore, we hypothesize complementary functions of fascin-1 and GFAP in the early and late phases of Sema5A-induced astrocytic differentiation of gliomas, respectively. In summary, Sema5A and plexin-B3 impede motility but promote differentiation of human gliomas. These effects are plausibly compromised in high-grade human astrocytomas in which Sema5A expression is markedly reduced, hence leading to infiltrative and anaplastic characteristics. This is evident by increased invasiveness of glioma cells when endogenous Sema5A is silenced. Therefore, Sema5A and plexin-B3 represent potential novel targets in counteracting glioma progression.


Assuntos
Citoesqueleto de Actina/metabolismo , Movimento Celular , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Moléculas de Adesão de Célula Nervosa/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Astrocitoma/genética , Astrocitoma/metabolismo , Astrocitoma/patologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Imunofluorescência , Adesões Focais , Proteína Glial Fibrilar Ácida/metabolismo , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Células HEK293 , Humanos , Immunoblotting , Imunoprecipitação , Proteínas de Membrana/genética , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/genética , Moléculas de Adesão de Célula Nervosa/genética , Fosforilação , Ligação Proteica , Proteína Quinase C/metabolismo , Transporte Proteico , Interferência de RNA , Semaforinas , Técnicas do Sistema de Duplo-Híbrido , Proteínas rac1 de Ligação ao GTP/genética
6.
J Neurosci ; 31(4): 1302-12, 2011 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-21273415

RESUMO

The modification of the neural cell adhesion molecule (NCAM) with polysialic acid (polySia) is tightly linked to neural development. Genetic ablation of the polySia-synthesizing enzymes ST8SiaII and ST8SiaIV generates polySia-negative but NCAM-positive (II(-/-)IV(-/-)) mice characterized by severe defects of major brain axon tracts, including internal capsule hypoplasia. Here, we demonstrate that misguidance of thalamocortical fibers and deficiencies of corticothalamic connections contribute to internal capsule defects in II(-/-)IV(-/-) mice. Thalamocortical fibers cross the primordium of the reticular thalamic nucleus (Rt) at embryonic day 14.5, before they fail to turn into the ventral telencephalon, thus deviating from their normal trajectory without passing through the internal capsule. At postnatal day 1, a reduction and massive disorganization of fibers traversing the Rt was observed, whereas terminal deoxynucleotidyl transferase dUTP nick end labeling and cleaved caspase-3 staining indicated abundant apoptotic cell death of Rt neurons at postnatal day 5. Furthermore, during postnatal development, the number of Rt neurons was drastically reduced in 4-week-old II(-/-)IV(-/-) mice, but not in the NCAM-deficient N(-/-) or II(-/-)IV(-/-)N(-/-) triple knock-out animals displaying no internal capsule defects. Thus, degeneration of the Rt in II(-/-)IV(-/-) mice may be a consequence of malformation of thalamocortical and corticothalamic fibers providing major excitatory input into the Rt. Indeed, apoptotic death of Rt neurons could be induced by lesioning corticothalamic fibers on whole-brain slice cultures. We therefore propose that anterograde transneuronal degeneration of the Rt in polysialylation-deficient, NCAM-positive mice is caused by defective afferent innervation attributable to thalamocortical pathfinding defects.


Assuntos
Córtex Cerebral/patologia , Neurônios/patologia , Ácidos Siálicos/genética , Tálamo/patologia , Vias Aferentes/anormalidades , Animais , Animais Recém-Nascidos , Apoptose , Axônios/patologia , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Dopamina/metabolismo , Cápsula Interna/anormalidades , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibras Nervosas/patologia , Moléculas de Adesão de Célula Nervosa/genética , Núcleos Talâmicos/embriologia , Núcleos Talâmicos/crescimento & desenvolvimento , Núcleos Talâmicos/patologia , Tálamo/embriologia , Tálamo/crescimento & desenvolvimento
7.
Cereb Cortex ; 18(5): 1125-38, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-17728262

RESUMO

The rat granular retrosplenial cortex (GRS) is a simplified cortex, with distinct stratification and, in the uppermost layers, distinct modularity. Thalamic and cortical inputs are segregated by layers and in layer 1 colocalize, respectively, with apical dendritic bundles originating from neurons in layers 2 or 5. To further investigate this organization, we turned to reelin-deficient reeler mouse and Shaking rat Kawasaki. We found that the disrupted lamination, evident in Nissl stains in these rodents, is in fact a patch-matrix mosaic of segregated afferents and dendrites. Patches consist of thalamocortical connections, visualized by vesicular glutamate transporter 2 (VGluT2) or AChE. The surrounding matrix consists of corticocortical terminations, visualized by VGluT1 or zinc. Dendrites concentrate in the matrix or patches, depending on whether they are OCAM positive (matrix) or negative (patches). In wild-type rodents and, presumably, mutants, OCAM(+) structures originate from layer 5 neurons. By double labeling for dendrites (filled by Lucifer yellow in fixed slice) and OCAM immunofluorescence, we ascertained 2 populations in reeler: dendritic branches either preferred (putative layer 5 neurons) or avoided (putative supragranular neurons) the OCAM(+) matrix. We conclude that input-target relationships are largely preserved in the mutant GRS and that dendrite-dendrite interactions involving OCAM influence the formation of the mosaic configuration.


Assuntos
Moléculas de Adesão Celular Neuronais/genética , Córtex Cerebral/patologia , Dendritos/patologia , Proteínas da Matriz Extracelular/genética , Camundongos Mutantes Neurológicos/anatomia & histologia , Proteínas do Tecido Nervoso/genética , Serina Endopeptidases/genética , Tálamo/patologia , Acetilcolinesterase/metabolismo , Animais , Agonistas de Aminoácidos Excitatórios , Feminino , Ácido Ibotênico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Imunoeletrônica , Moléculas de Adesão de Célula Nervosa/genética , Moléculas de Adesão de Célula Nervosa/metabolismo , Vias Neurais , Células Piramidais/metabolismo , Células Piramidais/patologia , Células Piramidais/ultraestrutura , Ratos , Ratos Mutantes , Ratos Wistar , Proteína Reelina , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
8.
Nutr Neurosci ; 9(3-4): 147-54, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17176637

RESUMO

ST8Sia IV (polysialyltransferase IV gene) encodes a key enzyme that is required for polysialic acid synthesis. Polysialic acid is a component of the neural cell adhesion molecule and is necessary for synaptic plasticity of neural cells. We characterized 5.3 kb of pig ST8Sia IV cDNA and determined its expression profile in different organs. In hippocampus, ST8Sia IV mRNA levels were increased approximately 4.5-fold in piglets with sialic acid as a milk supplement, which suggested that exogenous sialic acid is a conditionally essential nutrient for early brain development. Extensive analyses were also performed among its orthologs from human, mouse, rat, chicken, frog and zebrafish. Our results supported that the piglet is a better animal model than other nonprimate species in the studies of ST8Sia IV related metabolism and nutrition in human infants. This pig cDNA provides a basis for uncovering the roles of ST8Sia IV during piglet development and maturation.


Assuntos
Suplementos Nutricionais , Ácido N-Acetilneuramínico/farmacocinética , Moléculas de Adesão de Célula Nervosa/genética , Sialiltransferases/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Sequência Conservada , Primers do DNA , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de Sequência , Suínos
9.
Zhong Xi Yi Jie He Xue Bao ; 4(2): 175-80, 2006 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-16529695

RESUMO

OBJECTIVE: To study the effects of Yiqi Huayu Recipe on neural cell adhesion molecule (N-CAM) in neuromuscular junctions during nerve regeneration in rats with lumbar nerve root compression. METHODS: The rats with lumbar nerve root compression were given Yiqi Huayu Recipe for 10, 20 and 30 days respectively. The distribution of N-CAM in neuromuscular junctions of soleus muscle in rats was examined with immunohistochemical method and confocal laser scanning microscopy technique. The acetylcholine receptor (AChR) was visualized with fluorescein-conjugated alpha-bungarotoxin (alpha-BTX). The overlap areas of N-CAM and AChR sites were measured with NIH image technique. RESULTS: The aggregates, sprouts and extensions of N-CAM in the neuromuscular junctions and the overlap areas of N-CAM and AChR sites in the Yiqi Huayu Recipe-treated group were all better improved than those in the untreated group. CONCLUSION: The expression of N-CAM is regulated according to the state of innervation for muscles. Yiqi Huayu Recipe may accelerate this nerve regeneration process.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Síndromes de Compressão Nervosa/metabolismo , Moléculas de Adesão de Célula Nervosa/biossíntese , Raízes Nervosas Espinhais , Animais , Animais Recém-Nascidos , Masculino , Regeneração Nervosa , Moléculas de Adesão de Célula Nervosa/genética , Junção Neuromuscular/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Colinérgicos/metabolismo
10.
Genes Brain Behav ; 5(1): 46-52, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16436188

RESUMO

The neural cell adhesion molecule (NCAM) plays important roles in development of the nervous system and in synaptic plasticity and memory formation in the adult. The present study sought to further investigate the role of NCAM in learning by testing habituation and footshock sensitization learning of the startle response (SR) in NCAM null mutant (NCAM-/-) and wildtype littermate (NCAM+/+) mice. Whereas habituation is a form of non-associative learning, footshock sensitization is induced by rapid contextual fear conditioning. Habituation was tested by repetitive presentation of acoustic and tactile startle stimuli. Although NCAM-/- mice showed differences in sensitivity in both stimulus modalities, habituation learning was intact in NCAM-/- mice, suggesting that NCAM does not play a role in the mechanisms underlying synaptic plasticity in the startle pathway. Footshock sensitization was elicited by presentation of electric footshocks between two series of acoustic stimuli. In contrast to habituation, footshock sensitization learning was attenuated in NCAM-/- mice: the acoustic SR increase after the footshocks was lower in the mutant than in wildtype mice, indicating that NCAM plays an important role in the relevant brain areas, such as amygdala and/or the hippocampus.


Assuntos
Aprendizagem por Associação/fisiologia , Habituação Psicofisiológica/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Reflexo de Sobressalto/fisiologia , Estimulação Acústica , Animais , Limiar Auditivo/fisiologia , Condicionamento Operante/fisiologia , Feminino , Habituação Psicofisiológica/genética , Audição/genética , Audição/fisiologia , Camundongos , Camundongos Knockout , Moléculas de Adesão de Célula Nervosa/genética , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Reflexo de Sobressalto/genética , Tato/genética , Tato/fisiologia
11.
Rheumatol Int ; 26(9): 818-27, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16307273

RESUMO

The interaction of resident tissue cells with migratory inflammatory cells is essential for the recruitment of immune effector cells to inflammatory sites. The sustained expression of adhesion molecules in the synovium of patients with chronic Lyme arthritis seems to contribute to this chronic inflammation. Whether cell adhesion molecules influence the early steps of Borreliosis is unclear. Therefore, we examined the expression of ICAM-1, ICAM-2, VCAM-1 and NCAM-1 in synovial cells exposed to two different Borrelia burgdorferi sensu stricto strains Geho and B31. The mRNA expression of ICAM-1, ICAM-2, VCAM-1 and NCAM-1 was not changed in synovial cells exposed to B31. Whereas ICAM-2 and VCAM-1 was upregulated, NCAM-1 mRNA was downregulated and ICAM-1 mRNA was unchanged by strain Geho. The ICAM-1 protein expression on the synovial cell surface was downregulated by both strains. Differential regulation of adhesion molecule mRNA, and subsequent high turnover or elevated shedding from the cell membrane may contribute to early pathogenesis in Lyme arthritis.


Assuntos
Antígenos CD/genética , Borrelia burgdorferi/patogenicidade , Moléculas de Adesão Celular/genética , Molécula 1 de Adesão Intercelular/genética , Moléculas de Adesão de Célula Nervosa/genética , Membrana Sinovial/microbiologia , Molécula 1 de Adesão de Célula Vascular/genética , Antígenos CD/metabolismo , Artrite/etiologia , Artrite/microbiologia , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Doença de Lyme/complicações , Doença de Lyme/microbiologia , Moléculas de Adesão de Célula Nervosa/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Membrana Sinovial/citologia , Membrana Sinovial/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
12.
Brain ; 124(Pt 12): 2393-406, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11701594

RESUMO

L1 cell adhesion molecule (L1CAM) gene mutations are associated with X-linked 'recessive' neurological syndromes characterized by spasticity of the legs. L1CAM knock-out mice show hypoplasia of the corticospinal tract and failure of corticospinal axonal decussation and projection beyond the cervical spinal cord. The aim of this study was to determine if similar neuropathology underlies the spastic diplegia of males hemizygous for L1CAM mutations. Studies were performed on eight carrier females and 10 hemizygous males. Transcranial magnetic stimulation excited the corticospinal tract and responses were recorded in biceps brachii and quadriceps femoris. In contralateral biceps and quadriceps the responses had high thresholds and delayed onset compared with normal subjects. Ipsilateral responses in biceps were smaller, with higher thresholds and delayed onsets relative to contralateral responses. Subthreshold corticospinal conditioning of the stretch reflex of biceps and quadriceps was abnormal in both hemizygous males and carrier females suggesting there may also be a reduced projection to inhibitory interneurones. Histological examination of post-mortem material from a 2-week-old male with an L1CAM mutation revealed normal corticospinal decussation and axonal projections to lumbar spinal segments. These data support a role for L1CAM in corticospinal tract development in hemizygous males and 'carrier' females, but do not support a critical role for L1CAM in corticospinal axonal guidance.


Assuntos
Axônios/fisiologia , Glicoproteínas de Membrana/genética , Moléculas de Adesão de Célula Nervosa/genética , Tratos Piramidais/citologia , Tratos Piramidais/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Estimulação Elétrica , Feminino , Proteína GAP-43/análise , Ligação Genética , Heterozigoto , Humanos , Lactente , Recém-Nascido , Complexo Antígeno L1 Leucocitário , Magnetismo , Masculino , Pessoa de Meia-Idade , Córtex Motor/fisiologia , Destreza Motora , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Mutação , Tratos Piramidais/química , Reflexo de Estiramento/fisiologia , Cromossomo X
13.
Mol Cell Neurosci ; 17(6): 983-1000, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11414788

RESUMO

By optimizing the previously described strategy for obtention of spheres enriched in PSA-NCAM+ precursors, we prepared PSA-NCAM-immunoselected cell populations from cerebral hemispheres of neonatal MBP-LacZ transgenic mice. These cells expressed Nestin, exhibited clonal expansion potential and formed spheres, which were initially enriched in PSA-NCAM+ cells but became enriched in GD3+ oligodendrocyte progenitors after 1 week in B104 contionned medium. One month after their periventricular transplantation into the brain of wild-type and/or shiverer newborn mice, cells from PSA-NCAM+ spheres exhibited a higher rostral migration potential than cells from GD3+ spheres, and clearly contributed to myelination in the olfactory bulb. In shiverer hosts, both sphere populations generated oligodendrocytes with similar myelination potential. In addition PSA-NCAM+ sphere cells generated GFAP+ astrocytes and NeuN+ neurons, depending on their site of insertion. These results evidence the high plasticity of newborn PSA-NCAM+ neural precursors and suggest that they are promising tools for cell therapy of CNS diseases, including myelin disorders.


Assuntos
Encéfalo/crescimento & desenvolvimento , Diferenciação Celular/fisiologia , Linhagem da Célula/fisiologia , Movimento Celular/fisiologia , Proteínas do Tecido Nervoso , Molécula L1 de Adesão de Célula Nervosa , Moléculas de Adesão de Célula Nervosa/metabolismo , Neurônios/transplante , Ácidos Siálicos/metabolismo , Transplante de Células-Tronco , Animais , Antígenos de Diferenciação/metabolismo , Astrócitos/citologia , Astrócitos/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Transplante de Tecido Encefálico/métodos , Agregação Celular/genética , Técnicas de Cultura de Células/métodos , Células Cultivadas/citologia , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Doenças do Sistema Nervoso Central/cirurgia , Células Clonais/citologia , Células Clonais/efeitos dos fármacos , Células Clonais/metabolismo , Meios de Cultura/farmacologia , Gangliosídeos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Sobrevivência de Enxerto/fisiologia , Proteínas de Filamentos Intermediários/metabolismo , Camundongos , Camundongos Transgênicos , Nestina , Moléculas de Adesão de Célula Nervosa/genética , Neurônios/citologia , Neurônios/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Ácidos Siálicos/genética , Células-Tronco/citologia , Células-Tronco/metabolismo , Tálamo/citologia , Tálamo/crescimento & desenvolvimento , Tálamo/cirurgia
14.
Infect Immun ; 69(6): 3692-6, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11349032

RESUMO

Squamous mucosal epithelial cells constitutively express calprotectin in the cytoplasm. To study how this antimicrobial protein complex confers epithelial resistance to invading bacteria, an epithelial cell line was stably transfected to express the calprotectin complex. Cells expressing calprotectin resist invasion by Listeria monocytogenes and Salmonella enterica serovar Typhimurium. Calprotectin expression was accompanied by altered actin organization, increased alpha3 integrin expression, and spreading cell morphology. In this study, we assessed whether calprotectin expression affects bacterial binding and uptake. Threefold-fewer Listeria organisms bound to the surfaces of calprotectin-expressing cells, and 10-fold fewer were localized intracellularly by immunofluorescence. Similarly, fewer Salmonella organisms bound to cells expressing calprotectin. Calprotectin-expressing and sham-transfected cells showed similar levels of expression of surface E-cadherin and intracellular adhesion molecule 1 (ICAM-1) by flow cytometry. Calprotectin-expressing transfectants expressed calprotectin on the cell surface as well as in the cytosol. In conclusion, two bacterial pathogens showed reduced binding to calprotectin-expressing epithelial cells. Calprotectin-expressing cells appeared to have internalized disproportionately fewer Listeria organisms, suggesting that reduced binding and translocation supplemented direct antimicrobial effects in calprotectin-expressing cells.


Assuntos
Aderência Bacteriana/efeitos dos fármacos , Células KB/microbiologia , Listeria monocytogenes/efeitos dos fármacos , Glicoproteínas de Membrana/farmacologia , Moléculas de Adesão de Célula Nervosa/farmacologia , Salmonella typhimurium/efeitos dos fármacos , Citometria de Fluxo , Humanos , Células KB/metabolismo , Complexo Antígeno L1 Leucocitário , Listeria monocytogenes/metabolismo , Listeria monocytogenes/patogenicidade , Listeriose/microbiologia , Glicoproteínas de Membrana/genética , Moléculas de Adesão de Célula Nervosa/genética , Infecções por Salmonella/microbiologia , Salmonella typhimurium/metabolismo , Salmonella typhimurium/patogenicidade , Transfecção
15.
Brain Res Dev Brain Res ; 126(1): 21-30, 2001 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-11172883

RESUMO

Dopaminergic neurons of the mouse mesencephalon originate in the ventricular zone and migrate radially along radial glia then tangentially along nerve fibers that express the neural cell adhesion molecule L1 to form the substantia nigra (A9 group) and ventral tegmental area (VTA) (A10 group). The role of L1 in migration of dopaminergic neuronal precursors was investigated in L1 knockout mice by tyrosine hydroxylase (TH) immunostaining. An altered rostrocaudal distribution of dopaminergic neurons was observed within the substantia nigra and VTA of L1-minus mice. In L1-minus mice at postnatal day 0, TH-positive cells were present abnormally in the dorsomedial mesencephalon, suggesting impaired migration. Axons projecting from the substantia nigra to the caudate putamen also exhibited an abnormal targeting pattern. There was no evidence of dopaminergic cell loss in the mutant SN. Abnormal localization of dopaminergic neurons in L1-minus mice was also evident in the zona incerta of the thalamus (A13 group), and the arcuate (A12) and periventricular nucleus (A14) of the hypothalamus. Cell bodies and axons in the substantia nigra, VTA, and hypothalamus of wild type mouse embryos expressed L1. These results suggested that L1 plays an important developmental role in the organization of dopaminergic neuronal cell groups in the mesencephalon and diencephalon.


Assuntos
Dopamina/fisiologia , Glicoproteínas de Membrana/genética , Moléculas de Adesão de Célula Nervosa/genética , Neurônios/citologia , Animais , Movimento Celular/fisiologia , Feminino , Hipotálamo/citologia , Hipotálamo/imunologia , Marcação In Situ das Extremidades Cortadas , Complexo Antígeno L1 Leucocitário , Masculino , Camundongos , Camundongos Knockout , Neurônios/enzimologia , Substância Negra/citologia , Substância Negra/embriologia , Tirosina 3-Mono-Oxigenase/análise , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/embriologia
16.
J Neurosci ; 20(20): 7682-90, 2000 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-11027229

RESUMO

Genes that control the specification and differentiation of the functionally specialized areas of the mammalian neocortex are likely expressed across the developing neocortex in graded or restricted patterns. To search for such genes we have performed a PCR-based differential display screen using RNAs from rostral neocortex, which included the primary motor area, and caudal neocortex, which included the primary visual area, of embryonic day 16 rats. We identified 82 differentially expressed gene fragments. Secondary screening by in situ hybridization confirmed that five fragments, representing four genes, are differentially expressed across developing rat neocortex. Two of the genes, chick ovalbumin upstream transcription factor I (COUP-TFI) and close homolog of L1 (CHL1), have been cloned previously, but their differential expression in cortex has not been reported. Sequences from the other two fragments suggest that they represent novel genes. The expression patterns include graded, restricted, and discontinuous expression with abrupt borders that might correlate with those of areas. The differential expression patterns of all four genes are established before the arrival of thalamocortical afferents, suggesting that they are independent of thalamic influence, and could direct or reflect arealization. In addition, COUP-TFI and CHL1 exhibit dynamic expression patterns that undergo substantial changes after thalamocortical afferents invade the cortical plate, suggesting that thalamic axons may influence their later expression. Postnatally, COUP-TFI is most prominently expressed in layer 4, in both rats and mice, and CHL1 is expressed in layer 5. COUP-TFI expression in cortex, and in ventral telencephalon and dorsal thalamus, suggests several possible causes for the loss of layer 4 neurons and the reduced thalamocortical projection reported in COUP-TFI knock-out mice.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Molécula L1 de Adesão de Célula Nervosa , Moléculas de Adesão de Célula Nervosa/biossíntese , Proteínas , Telencéfalo/metabolismo , Fatores de Transcrição/biossíntese , Animais , Fator I de Transcrição COUP , Moléculas de Adesão Celular , Proteínas de Ligação a DNA/genética , Perfilação da Expressão Gênica , Hipocampo/citologia , Hipocampo/embriologia , Hipocampo/metabolismo , Hibridização In Situ , Camundongos , Camundongos Endogâmicos ICR , Neocórtex/citologia , Neocórtex/embriologia , Neocórtex/metabolismo , Moléculas de Adesão de Célula Nervosa/genética , Especificidade de Órgãos , Fragmentos de Peptídeos/biossíntese , Fragmentos de Peptídeos/genética , Ratos , Ratos Sprague-Dawley , Córtex Somatossensorial/citologia , Córtex Somatossensorial/embriologia , Córtex Somatossensorial/metabolismo , Telencéfalo/citologia , Telencéfalo/embriologia , Tálamo/citologia , Tálamo/embriologia , Tálamo/metabolismo , Fatores de Transcrição/genética
17.
Am J Med Genet ; 92(1): 40-6, 2000 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-10797421

RESUMO

Mutations in L1CAM, the gene encoding the L1 neuronal cell adhesion molecule, lead to an X-linked trait characterized by one or more of the symptoms of hydrocephalus, adducted thumbs, agenesis or hypoplasia of corpus callosum, spastic paraplegia, and mental retardation (L1-disease). We screened 153 cases with prenatally or clinically suspected X-chromosomal hydrocephalus for L1CAM mutations by SSCP analysis of the 28 coding exons and regulatory elements in the 5'-untranslated region of the gene. Forty-six pathogenic mutations were found (30.1% detection rate), the majority consisting of nonsense, frameshift, and splice site mutations. In eight cases, segregation analysis disclosed recent de novo mutations. Statistical analysis of the data indicates a significant effect on mutation detection rate of (i) family history, (ii) number of L1-disease typical clinical findings, and (iii) presence or absence of signs not typically associated with L1CAM-disease. Whereas mutation detection rate was 74.2% for patients with at least two additional cases in the family, only 16 mutations were found in the 102 cases with negative family history (15.7% detection rate). Our data suggest a higher than previously assumed contribution of L1CAM mutations in the pathogenesis of the heterogeneous group of congenital hydrocephalus.


Assuntos
Anormalidades Múltiplas/genética , Glicoproteínas de Membrana/genética , Moléculas de Adesão de Célula Nervosa/genética , Cromossomo X/genética , Adolescente , Adulto , Agenesia do Corpo Caloso , Processamento Alternativo/genética , Animais , Células COS , Criança , Pré-Escolar , Chlorocebus aethiops , Análise Mutacional de DNA , DNA Complementar/química , DNA Complementar/genética , Saúde da Família , Feminino , Mutação da Fase de Leitura , Ligação Genética , Genótipo , Humanos , Hidrocefalia , Lactente , Deficiência Intelectual , Complexo Antígeno L1 Leucocitário , Masculino , Dados de Sequência Molecular , Mutação , Mutação de Sentido Incorreto , Paraplegia , Fenótipo , Polimorfismo Genético , Polimorfismo Conformacional de Fita Simples , RNA Mensageiro/genética , Análise de Sequência de DNA , Polegar/anormalidades
18.
Int J Dev Neurosci ; 17(2): 121-30, 1999 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10221671

RESUMO

L1 is a murine multidomain glycoprotein implicated in cell aggregation, fasciculation. neurite outgrowth and synaptogenesis. Laminin, a trimeric polypeptide, is implicated in neuronal survival, growth cone guidance, neurite outgrowth and cell differentiation. Laminin can also interact with the cell adhesion molecule L1. Their expressions were investigated from embryonic day 15 (E15) to adult in the rat hypophysis, and in adult neurohemal zones. Detected in the neural lobe from E17, the L1 immunoreactivity increased during prenatal development and persisted in adulthood mainly related to the neuropeptidergic fibers. Pituicytes were only labelled on the plasmalemma apposed to axons. In the intermediate lobe, L1 appeared at birth on folliculo-stellate cells extensions, constituting a network which densified during postnatal development. L1 is also expressed in all neurohemal areas on neuronal profiles. Laminin was clearly detectable in the hypophysis at E15 before the first blood vessels penetrate the Rathke pouch. At E20, all the basal membranes of the blood vessels were stained. In the intermediate lobe, a spotted laminin immunoreactivity was detected at E21. At this stage, we observed the staining of intercellular spaces and the intracellular labelling of melanotrophs, concerning reticulum or vesicles. The staining of melanotrophs seemed to maintain during adulthood. In contrast with blood vessels of the adult cerebral tissue, adult capillaries of the neural lobe and the others neuro-hemal zones were intensely labelled with the anti-laminin antibody. These results suggest that neurite outgrowth and neurite guidance could be promoted by L1 and laminin in the neurointermediate lobe. The "intercellular tunnels" could also be an important guidance cue for migrating cells in the intermediate lobe. These data also demonstrate that melanotrophic cells. secreting the laminin, have a role in the ontogenesis of the gland. Finally, we suggest that L1 and laminin can collaborate to reinforce "neurons-capillaries" interactions in neurohemal zones.


Assuntos
Proteínas Fetais/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Laminina/biossíntese , Glicoproteínas de Membrana/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Moléculas de Adesão de Célula Nervosa/biossíntese , Sistemas Neurossecretores/embriologia , Hipófise/embriologia , Animais , Movimento Celular , Proteínas Fetais/genética , Idade Gestacional , Hipotálamo/embriologia , Hipotálamo/crescimento & desenvolvimento , Hibridização In Situ , Laminina/genética , Complexo Antígeno L1 Leucocitário , Glicoproteínas de Membrana/genética , Neovascularização Fisiológica , Proteínas do Tecido Nervoso/genética , Moléculas de Adesão de Célula Nervosa/genética , Neuritos/fisiologia , Sistemas Neurossecretores/crescimento & desenvolvimento , Sistemas Neurossecretores/metabolismo , Hipófise/irrigação sanguínea , Hipófise/crescimento & desenvolvimento , Hipófise/inervação , Hipófise/metabolismo , Ratos , Ratos Wistar
19.
Eur J Neurosci ; 11(3): 813-26, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10103075

RESUMO

The close homologue of L1 (CHL1), a member of the L1 family of neural adhesion molecules, is first expressed at times of neurite outgrowth during brain development, and is detectable in subpopulations of neurons, astrocytes, oligodendrocyte precursors and Schwann cells of the mouse and rat. Aggregation assays with CHL1-transfected cells show that CHL1 does not promote homophilic adhesion or does it mediate heterophilic adhesion with L1. CHL1 promotes neurite outgrowth by hippocampal and small cerebellar neurons in substrate-bound and soluble form. The observation that CHL1 and L1 show overlapping, but also distinct patterns of synthesis in neurons and glia, suggests differential effects of L1-like molecules on neurite outgrowth.


Assuntos
Química Encefálica/fisiologia , Proteínas do Tecido Nervoso/genética , Molécula L1 de Adesão de Célula Nervosa , Moléculas de Adesão de Célula Nervosa/genética , Neuritos/química , Proteínas , Animais , Western Blotting , Células COS , Moléculas de Adesão Celular , Drosophila , Expressão Gênica/fisiologia , Hipocampo/química , Hipocampo/citologia , Hibridização In Situ , Camundongos , Camundongos Endogâmicos ICR , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/metabolismo , Moléculas de Adesão de Célula Nervosa/análise , Moléculas de Adesão de Célula Nervosa/metabolismo , Neuritos/metabolismo , Neurônios/química , Neurônios/fisiologia , Neurônios/ultraestrutura , Oligodendroglia/citologia , Nervos Periféricos/química , Nervos Periféricos/citologia , Nervos Periféricos/metabolismo , Ligação Proteica/fisiologia , RNA Mensageiro/análise , Coelhos , Ratos , Tálamo/química , Tálamo/citologia , Transfecção
20.
Am J Physiol ; 275(2): F255-61, 1998 08.
Artigo em Inglês | MEDLINE | ID: mdl-9691016

RESUMO

Urine produced by normal human kidneys is almost always supersaturated with respect to calcium oxalate (CaOx), the most common constituent of human kidney stones. Crystallization, with risk of renal damage and kidney stones, appears to be affected by molecules in urine that retard nucleation, growth, aggregation, and renal cell adherence of CaOx. The repertoire of such molecules is incompletely known. We have purified a 28-kDa protein from urine using salt precipitation, preparative isoelectric focusing, and sizing chromatography. Amino acid composition and NH2-terminal amino sequence analysis showed complete homology to calgranulin. Calgranulin was found to be a potent inhibitor of CaOx crystal growth (44% of control) and aggregation (50% of control) in the nanomolar range. Calgranulin cDNA was cloned from a human kidney expression library. Western analysis of human and rat kidney homogenates and mRNA temporal expression from two independent renal epithelial cell lines showed that calgranulin is produced in the kidney. Given its urinary abundance and potency, calgranulin may contribute importantly to the normal urinary inhibition of crystal growth and aggregation and therefore to the renal defense against clinical stone disease.


Assuntos
Oxalato de Cálcio/química , Proteínas de Ligação ao Cálcio/biossíntese , Rim/metabolismo , Glicoproteínas de Membrana/biossíntese , Moléculas de Adesão de Célula Nervosa/biossíntese , Animais , Northern Blotting , Proteínas de Ligação ao Cálcio/isolamento & purificação , Proteínas de Ligação ao Cálcio/fisiologia , Linhagem Celular , Cristalização , DNA Complementar , Eletroforese Descontínua , Eletroforese em Gel Bidimensional , Biblioteca Gênica , Humanos , Focalização Isoelétrica , Complexo Antígeno L1 Leucocitário , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/isolamento & purificação , Glicoproteínas de Membrana/urina , Moléculas de Adesão de Célula Nervosa/genética , Moléculas de Adesão de Célula Nervosa/isolamento & purificação , Moléculas de Adesão de Célula Nervosa/urina , Ratos , Valores de Referência
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