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1.
Development ; 137(23): 4101-10, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21062867

RESUMO

Polarized radial glia are crucial to the formation of the cerebral cortex. They serve as neural progenitors and as guides for neuronal placement in the developing cerebral cortex. The maintenance of polarized morphology is essential for radial glial functions, but the extent to which the polarized radial glial scaffold is static or dynamic during corticogenesis remains an open question. The developmental dynamics of radial glial morphology, inter-radial glial interactions during corticogenesis, and the role of the cell polarity complexes in these activities remain undefined. Here, using real-time imaging of cohorts of mouse radial glia cells, we show that the radial glial scaffold, upon which the cortex is constructed, is highly dynamic. Radial glial cells within the scaffold constantly interact with one another. These interactions are mediated by growth cone-like endfeet and filopodia-like protrusions. Polarized expression of the cell polarity regulator Cdc42 in radial glia regulates glial endfeet activities and inter-radial glial interactions. Furthermore, appropriate regulation of Gsk3 activity is required to maintain the overall polarity of the radial glia scaffold. These findings reveal dynamism and interactions among radial glia that appear to be crucial contributors to the formation of the cerebral cortex. Related cell polarity determinants (Cdc42, Gsk3) differentially influence radial glial activities within the evolving radial glia scaffold to coordinate the formation of cerebral cortex.


Assuntos
Comunicação Celular , Polaridade Celular , Córtex Cerebral/embriologia , Quinase 3 da Glicogênio Sintase/metabolismo , Neuroglia/citologia , Neuroglia/enzimologia , Proteína cdc42 de Ligação ao GTP/metabolismo , Animais , Bioensaio , Forma Celular , Córtex Cerebral/citologia , Córtex Cerebral/enzimologia , Embrião de Mamíferos/citologia , Embrião de Mamíferos/enzimologia , Glicogênio Sintase Quinase 3 beta , Cones de Crescimento/metabolismo , Integrases/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Nestina , Pseudópodes/enzimologia
2.
Proc Natl Acad Sci U S A ; 107(12): 5622-7, 2010 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-20212127

RESUMO

Neuregulin-1 (NRG1) and Disrupted-in-Schizophrenia-1 (DISC1) are promising susceptibility factors for schizophrenia. Both are multifunctional proteins with roles in a variety of neurodevelopmental processes, including progenitor cell proliferation, migration, and differentiation. Here, we provide evidence linking these factors together in a single pathway, which is mediated by ErbB receptors and PI3K/Akt. We show that signaling by NRG1 and NRG2, but not NRG3, increase expression of an isoform of DISC1 in vitro. Receptors ErbB2 and ErbB3, but not ErbB4, are responsible for transducing this effect, and PI3K/Akt signaling is also required. In NRG1 knockout mice, this DISC1 isoform is selectively reduced during neurodevelopment. Furthermore, a similar decrease in DISC1 expression is seen in beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) knockout mice, in which NRG1/Akt signaling is reportedly impaired. In contrast to neuronal DISC1 that was reported and characterized, expression of DISC1 in other types of cells in the brain has not been addressed. Here we demonstrate that DISC1, like NRG and ErbB proteins, is expressed in neurons, astrocytes, oligodendrocytes, microglia, and radial progenitors. These findings may connect NRG1, ErbBs, Akt, and DISC1 in a common pathway, which may regulate neurodevelopment and contribute to susceptibility to schizophrenia.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuregulina-1/metabolismo , Secretases da Proteína Precursora do Amiloide/deficiência , Secretases da Proteína Precursora do Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/deficiência , Ácido Aspártico Endopeptidases/genética , Astrócitos/metabolismo , Encéfalo/metabolismo , Linhagem Celular , Células Cultivadas , Humanos , Camundongos , Camundongos Knockout , Microglia/metabolismo , Proteínas do Tecido Nervoso/genética , Neuregulina-1/deficiência , Neuregulina-1/genética , Neurogênese , Neurônios/metabolismo , Oligodendroglia/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Esquizofrenia/etiologia , Transdução de Sinais
3.
Proc Natl Acad Sci U S A ; 106(18): 7595-600, 2009 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-19383784

RESUMO

Cortical GABAergic interneurons, most of which originate in the ganglionic eminences, take distinct tangential migratory trajectories into the developing cerebral cortex. However, the ligand-receptor systems that modulate the tangential migration of distinct groups of interneurons into the emerging cerebral wall remain unclear. Here, we show that netrin-1, a diffusible guidance cue expressed along the migratory routes traversed by GABAergic interneurons, interacts with alpha3beta1 integrin to promote interneuronal migration. In vivo analysis of interneuron-specific alpha3beta1 integrin, netrin-1-deficient mice (alpha3(lox/-)Dlx5/6-CIE, netrin-1(-/-)) reveals specific deficits in the patterns of interneuronal migration along the top of the developing cortical plate, resulting in aberrant interneuronal positioning throughout the cerebral cortex and hippocampus of conditional alpha3(lox/-)Dlx5/6-CIE, netrin-1(-/-) mice. These results indicate that specific guidance mechanisms, such as netrin-1-alpha3beta1 integrin interactions, modulate distinct routes of interneuronal migration and the consequent positioning of groups of cortical interneurons in the developing cerebral cortex.


Assuntos
Movimento Celular , Córtex Cerebral/crescimento & desenvolvimento , Integrina alfa3beta1/metabolismo , Interneurônios/fisiologia , Fatores de Crescimento Neural/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Movimento Celular/genética , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Interneurônios/metabolismo , Camundongos , Camundongos Knockout , Fatores de Crescimento Neural/genética , Netrina-1 , Proteínas Supressoras de Tumor/genética , Ácido gama-Aminobutírico/metabolismo
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