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1.
Brain Struct Funct ; 222(3): 1367-1384, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27510895

RESUMO

Developmental dyslexia is a common disorder with a strong genetic component, but the underlying molecular mechanisms are still unknown. Several candidate dyslexia-susceptibility genes, including KIAA0319, DYX1C1, and DCDC2, have been identified in humans. RNA interference experiments targeting these genes in rat embryos have shown impairments in neuronal migration, suggesting that defects in radial cortical migration could be involved in the disease mechanism of dyslexia. Here we present the first characterisation of a Kiaa0319 knockout mouse line. Animals lacking KIAA0319 protein do not show anatomical abnormalities in any of the layered structures of the brain. Neurogenesis and radial migration of cortical projection neurons are not altered, and the intrinsic electrophysiological properties of Kiaa0319-deficient neurons do not differ from those of wild-type neurons. Kiaa0319 overexpression in cortex delays radial migration, but does not affect final neuronal position. However, knockout animals show subtle differences suggesting possible alterations in anxiety-related behaviour and in sensorimotor gating. Our results do not reveal a migration disorder in the mouse model, adding to the body of evidence available for Dcdc2 and Dyx1c1 that, unlike in the rat in utero knockdown models, the dyslexia-susceptibility candidate mouse homolog genes do not play an evident role in neuronal migration. However, KIAA0319 protein expression seems to be restricted to the brain, not only in early developmental stages but also in adult mice, indicative of a role of this protein in brain function. The constitutive and conditional knockout lines reported here will be useful tools for further functional analyses of Kiaa0319.


Assuntos
Movimento Celular/genética , Dislexia/genética , Dislexia/patologia , Neocórtex/patologia , Proteínas do Tecido Nervoso/deficiência , Neurônios/fisiologia , Fatores Etários , Animais , Animais Recém-Nascidos , Ansiedade/etiologia , Ansiedade/genética , Encéfalo/metabolismo , Adaptação à Escuridão/genética , Modelos Animais de Doenças , Dislexia/complicações , Eletroporação , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Genótipo , Técnicas In Vitro , Antígeno Ki-67/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Potenciais da Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neocórtex/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/genética , Fator de Transcrição PAX6/metabolismo , Técnicas de Patch-Clamp , Gravidez , Inibição Pré-Pulso/genética , Interferência de RNA , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Filtro Sensorial/genética , Proteínas com Domínio T/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
2.
Ann Anat ; 195(5): 431-40, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23756022

RESUMO

Central nervous system development is controlled by highly conserved homeoprotein transcription factors including HOX and TALE (Three Amino acid Loop Extension). TALE proteins are primarily known as HOX-cofactors and play key roles in cell proliferation, differentiation and organogenesis. MEIS1 is a TALE member with established expression in the developing central nervous system. MEIS1 is essential for embryonic development and Meis1 knockout mice dies at embryonic day (E) 14.5. However, Meis1/MEIS1 expression in the devolving forebrain, at this critical time-point has not been studied. Here, for the first time we characterize the region-specific expression of MEIS1 in E14.5 mouse forebrain, filling the gap of MEIS1 expression profile between E12.5 and E16.5. Previously, we reported MEIS1 transcriptional regulatory role in neuronal differentiation and established forebrain-derived neural stem cells (NSC) for gene therapy application of neuronal genes. Here, we show the dynamic expression of Meis1/MEIS1 during the differentiation of forebrain-derived NSC toward a glial lineage. Our results show that Meis1/MEIS1 expression is induced during NSC differentiation and is expressed in both differentiated neurons and astrocytes. Confirming these results, we detected MEIS1 expression in primary cultures of in vivo differentiated cortical neurons and astrocytes. We further demonstrate Meis1/MEIS1 expression relative to other TALE family members in the forebrain-derived NSC in the absence of Hox genes. Our data provide evidence that forebrain-derived NSC can be used as an accessible in vitro model to study the expression and function of TALE proteins, supporting their potential role in modulating NSC self-renewal and differentiation.


Assuntos
Proteínas de Homeodomínio/biossíntese , Proteínas de Neoplasias/biossíntese , Células-Tronco Neurais/metabolismo , Prosencéfalo/citologia , Prosencéfalo/metabolismo , Animais , Astrócitos/metabolismo , Western Blotting , Diferenciação Celular , Separação Celular , Células Cultivadas , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Proteína Meis1 , Gravidez , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Fixação de Tecidos
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