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Cereb Cortex ; 24(11): 2835-47, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23749873


Malformations of cortical development can arise when projection neurons generated in the germinal zones fail to migrate properly into the cortical plate. This process is critically dependent on the Reelin glycoprotein, which when absent leads to an inversion of cortical layers and blurring of borders. Reelin has other functions including supporting neuron migration and maintaining their trajectories; however, the precise role on glial fiber-dependent or -independent migration of neurons remains controversial. In this study, we wish to test the hypothesis that migrating cortical neurons at different levels of the cortical wall have differential responses to Reelin. We exposed neurons migrating across the cortical wall to exogenous Reelin and monitored their migratory behavior using time-lapse imaging. Our results show that, in the germinal zones, exogenous Reelin retarded neuron migration and altered their trajectories. This behavior is in contrast to the response of neurons located in the intermediate zone (IZ), possibly because Reelin receptors are not expressed in this zone. In the reeler cortex, Reelin receptors are expressed in the IZ and exposure to exogenous Reelin was able to rescue the migratory defect. These studies demonstrate that migrating neurons have nonequivalent responses to Reelin depending on their location within the cortical wall.

Moléculas de Adesão Celular Neuronais/farmacologia , Movimento Celular/efeitos dos fármacos , Córtex Cerebral/citologia , Proteínas da Matriz Extracelular/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Serina Endopeptidases/farmacologia , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas Adaptadoras de Transporte Vesicular/genética , Fatores Etários , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Análise de Variância , Animais , Linhagem Celular Transformada , Movimento Celular/genética , Eletroporação , Embrião de Mamíferos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Técnicas In Vitro , Camundongos , Camundongos Mutantes Neurológicos , Microscopia Confocal , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Cultura de Órgãos , Transfecção
Cereb Cortex ; 21(5): 1018-27, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-20847150


The Reelin signaling pathway is essential for proper cortical development, but it is unclear to whether Reelin function is primarily important for cortical layering or neuron migration. It has been proposed that Reelin is perhaps required only for somal translocation but not glial-dependent locomotion. This implies that the location of neurons responding to Reelin is restricted to the outer regions of the cortical plate (CP). To determine whether Reelin is required for migration outside of the CP, we used time-lapse imaging to track the behavior of cells undergoing locomotion in the germinal zones. We focused on the migratory activity in the ventricular/subventricular zones where the first transition of bipolar to multipolar migration occurs and where functional Reelin receptors are known to be expressed. Despite Reelin loss, neurons had no difficulty in undergoing radial migration and indeed displayed greater migratory speed. Additionally, compared with the wild-type, reeler neurons displayed altered trajectories with greater deviation from a radial path. These results suggest that Reelin loss has early consequences for migration in the germinal zones that are portrayed as defective radial trajectories and migratory speeds. Together, these abnormalities can give rise to the increased cell dispersion observed in the reeler cortex.

Moléculas de Adesão Celular Neuronais/deficiência , Movimento Celular/genética , Proteínas da Matriz Extracelular/deficiência , Neocórtex/citologia , Proteínas do Tecido Nervoso/deficiência , Neurônios/patologia , Serina Endopeptidases/deficiência , Animais , Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/genética , Camundongos , Camundongos Mutantes Neurológicos , Neocórtex/metabolismo , Neocórtex/patologia , Proteínas do Tecido Nervoso/genética , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/fisiopatologia , Neurônios/citologia , Neurônios/fisiologia , Técnicas de Cultura de Órgãos , Serina Endopeptidases/genética , Transmissão Sináptica/genética
Glia ; 56(3): 306-17, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18080292


This work investigates the role of NT-3 in peripheral myelination. Recent articles, based in vitro, propose that NT-3 acting through its high-affinity receptor TrkC may act to inhibit myelin formation by enhancing Schwann cell motility and/or migration. Here, we investigate this hypothesis in vivo by examining myelination formation in NT-3 mutant mice. On the day of birth, soon after the onset of myelination, axons showed normal ensheathment by Schwann cells, no change in the proportion of axons which had begun to myelinate, and no change in either myelin thickness or number of myelin lamellae. However in postnatal day 21 mice, when myelination is substantially complete, we observed an unexpected reduction in mRNA and protein levels for MAG and P(0), and in myelin thickness. This is the opposite result to that predicted from previous in vitro studies, where removal of an inhibitory NT-3 signal would have been expected to enhance myelination. These results suggest that, in vivo, the importance of NT-3 as a major support factor for Schwann cells (Meier et al., (1999) J Neurosci 19:3847-3859) over-rides its potential role as an myelin inhibitor, with the net effect that loss of NT-3 results in degradation of Schwann cell functions, including myelination. In support of this idea, Schwann cells of NT-3 null mutants showed increased expression of activated caspase-3. Finally, we observed significant reduction in width of the Schwann cell periaxonal collar in NT-3 mutant animals suggesting that loss of NT-3 and resulting reduction in MAG levels may alter signaling at the axon-glial interface.

Apoptose/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteína P0 da Mielina/metabolismo , Glicoproteína Associada a Mielina/metabolismo , Fatores de Crescimento Neural/deficiência , Células de Schwann/fisiologia , Animais , Animais Recém-Nascidos , Axônios/ultraestrutura , Caspase 3/metabolismo , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Transmissão/métodos , Proteína P0 da Mielina/genética , Glicoproteína Associada a Mielina/genética , Fatores de Crescimento Neural/metabolismo , Proteínas de Neurofilamentos/metabolismo , Nervos Periféricos/ultraestrutura , Células de Schwann/ultraestrutura , Estatísticas não Paramétricas