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1.
J Neurosci ; 30(41): 13883-94, 2010 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-20943929

RESUMO

Previous studies have defined a requirement for Sonic hedgehog (Shh) signaling in patterning the ventral telencephalon, a major source of the neuronal diversity found in the mature telencephalon. The zinc finger transcription factor Gli3 is a critical component of the Shh signaling pathway and its loss causes major defects in telencephalic development. Gli3 is expressed in a graded manner along the dorsoventral axis of the telencephalon but it is unknown whether Gli3 expression levels are important for dorsoventral telencephalic patterning. To address this, we used the Gli3 hypomorphic mouse mutant Polydactyly Nagoya (Pdn). We show that in Pdn/Pdn embryos, the telencephalic expression of Gli3 remains graded, but Gli3 mRNA and protein levels are reduced, resulting in an upregulation of Shh expression and signaling. These changes mainly affect the development of the lateral ganglionic eminence (LGE), with some disorganization of the medial ganglionic eminence mantle zone. The pallial/subpallial boundary is shifted dorsally and the production of postmitotic neurons is reduced. Moreover, LGE pioneer neurons that guide corticofugal axons into the LGE do not form properly, delaying the entry of corticofugal axons into the ventral telencephalon. Pdn/Pdn mutants also show severe pathfinding defects of thalamocortical axons in the ventral telencephalon. Transplantation experiments demonstrate that the intrinsic ability of the Pdn ventral telencephalon to guide thalamocortical axons is compromised. We conclude that correct Gli3 levels are particularly important for the LGE's growth, patterning, and development of axon guidance capabilities.


Assuntos
Axônios/metabolismo , Padronização Corporal/fisiologia , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Telencéfalo/crescimento & desenvolvimento , Animais , Western Blotting , Imuno-Histoquímica , Hibridização In Situ , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Telencéfalo/metabolismo , Proteína Gli3 com Dedos de Zinco
2.
ASN Neuro ; 1(4)2009 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-19715557

RESUMO

Recently, several in vitro studies have shown that the golli-myelin basic proteins regulate Ca2+ homoeostasis in OPCs (oligodendrocyte precursor cells) and immature OLs (oligodendrocytes), and that a number of the functions of these cells are affected by cellular levels of the golli proteins. To determine the influence of golli in vivo on OL development and myelination, a transgenic mouse was generated in which the golli isoform J37 was overexpressed specifically within OLs and OPCs. The mouse, called JOE (J37-overexpressing), is severely hypomyelinated between birth and postnatal day 50. During this time, it exhibits severe intention tremors that gradually abate at later ages. After postnatal day 50, ultrastructural studies and Northern and Western blot analyses indicate that myelin accumulates in the brain, but never reaches normal levels. Several factors appear to underlie the extensive hypomyelination. In vitro and in vivo experiments indicate that golli overexpression causes a significant delay in OL maturation, with accumulation of significantly greater numbers of pre-myelinating OLs that fail to myelinate axons during the normal myelinating period. Immunohistochemical studies with cell death and myelin markers indicate that JOE OLs undergo a heightened and extended period of cell death and are unable to effectively myelinate until 2 months after birth. The results indicate that increased levels of golli in OPC/OLs delays myelination, causing significant cell death of OLs particularly in white matter tracts. The results provide in vivo evidence for a significant role of the golli proteins in the regulation of maturation of OLs and normal myelination.

3.
Eur J Neurosci ; 25(1): 17-30, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17241263

RESUMO

The first postmitotic neurons in the developing neocortex establish the preplate layer. These early-born neurons have a significant influence on the circuitry of the developing cortex. However, the exact timing and trajectory of their projections, between cortical hemispheres and intra- and extra-cortical regions, remain unresolved. Here, we describe the creation of a transgenic mouse using a 1.3 kb golli promoter element of the myelin basic protein gene to target expression of a tau-green fluorescent protein (GFP) fusion protein in the cell bodies and processes of pioneer cortical neurons. During embryonic and early neonatal development, the timing and patterning of process extension from these neurons was examined. Analysis of tau-GFP fluorescent fibers revealed that progression of early labeled projections was interrupted unexpectedly by transient pauses at the corticostriatal and telencephalic-diencephalic boundaries before invading the thalamus just prior to birth. After birth the pioneering projections differentially invaded the thalamus, excluding some nuclei, e.g. medial and lateral geniculate, until postnatal days 10-14. Early labeled projections were also found to cross to the contralateral hemisphere as well as to the superior colliculus. These results indicate that early corticothalamic projections appear to pause before invading specific subcortical regions during development, that there is developmental regulation of innervation of individual thalamic nuclei, and that these early-generated neurons also establish early projections to commissural and subcortical targets.


Assuntos
Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Vias Neurais , Proteínas tau/metabolismo , Animais , Animais Recém-Nascidos , Mapeamento Encefálico , Contagem de Células/métodos , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Embrião de Mamíferos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Vias Neurais/embriologia , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/metabolismo , Neurônios/metabolismo , Proteínas tau/genética
4.
Novartis Found Symp ; 288: 212-24; discussion 224-9, 276-81, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18494261

RESUMO

Building the brain is like erecting a house of cards. The early connections provide the foundation of the adult structure, and disruption of these may be the source of many developmental flaws. Cerebral cortical developmental disorders (including schizophrenia and autism) and perinatal injuries involve cortical neurons with early connectivity. The major hindrance of progress in understanding the early neural circuits during cortical development and disease has been the lack of reliable markers for specific cell populations. Due to the advance of powerful approaches in gene expression analysis and the utility of models with reporter gene expressions in specific cortical cell types, our knowledge of the early cortical circuits is rapidly increasing. With focus on the sub-plate, layer VI and layer V projection neurons, we shall illustrate the progress made in the understanding of their neurochemical properties, physiological characteristics and their integration into the early intracortical and extracortical circuitry. This field benefited from recent developments in mouse genetics in generating models with subtype specific gene expression patterns, powerful cell dissection and separation methods combined with microarray analysis. The emergence of cortical cell type specific biomarkers will not only help neuropathological diagnosis, but will also eventually reveal the causal relations in the pathogenesis of various cortical developmental disorders.


Assuntos
Córtex Cerebral/embriologia , Genes Controladores do Desenvolvimento/fisiologia , Rede Nervosa/embriologia , Animais , Axônios/fisiologia , Diferenciação Celular , Córtex Cerebral/metabolismo , Embrião de Mamíferos , Humanos , Modelos Biológicos , Rede Nervosa/metabolismo , Neurônios/fisiologia , Fatores de Tempo
5.
J Neurosci ; 25(30): 7004-13, 2005 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-16049176

RESUMO

The myelin basic protein (MBP) gene encodes two families of proteins, the classic MBP constituents of myelin and the golli-MBPs, the function of which is less well understood. In this study, targeted ablation of the golli-MBPs, but not the classic MBPs, resulted in a distinct phenotype unlike that of knock-outs (KOs) of the classic MBPs or other myelin proteins. Although the golli KO animals did not display an overt dysmyelinating phenotype, they did exhibit delayed and/or hypomyelination in selected areas of the brain, such as the visual cortex and the optic nerve, as determined by Northern and Western blots and immunohistochemical analysis with myelin protein markers. Hypomyelination in some areas, such as the visual cortex, persisted into adulthood. Ultrastructural analysis of the KOs confirmed both the delay and hypomyelination and revealed abnormalities in myelin structure and in some oligodendrocytes. Abnormal visual-evoked potentials indicated that the hypomyelination in the visual cortex had functional consequences in the golli KO brain. Evidence that the abnormal myelination in these animals was a consequence of intrinsic problems with the oligodendrocyte was indicated by an impaired ability of oligodendrocytes to form myelin sheets in culture and by the presence of abnormal Ca2+ transients in purified cortical oligodendrocytes studied in vitro. The Ca2+ results reported in this study complement previous results implicating golli proteins in modulating intracellular signaling in T-cells. Together, all these findings suggest a role for golli proteins in oligodendrocyte differentiation, migration, and/or myelin elaboration in the brain.


Assuntos
Bainha de Mielina/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Oligodendroglia/patologia , Nervo Óptico/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia , Córtex Visual/patologia , Animais , Cálcio/metabolismo , Feminino , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Eletrônica , Proteína Básica da Mielina , Fibras Nervosas Mielinizadas/patologia , Fibras Nervosas Mielinizadas/ultraestrutura , Oligodendroglia/metabolismo
7.
Neurochem Res ; 29(5): 997-1002, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15139298

RESUMO

In addition to classic proteolipid protein (PLP) and DM20, the mouse myelin proteolipid gene produces the sr-PLP and sr-DM20 proteins. The sr-isoforms are localized to the cell bodies of both oligodendrocytes and neurons. However, they are expressed to a greater extent in neurons than they are in glia. In this study, we examined expression of the sr-proteolipids in the mouse embryo using immunohistochemistry with an sr-PLP/DM20 specific antibody. Widespread expression of the sr-proteins was found in many nonmyelinating cell types. In particular, strong immunoreactivity was detected in motor neurons of both the autonomic and somatic nervous systems as well as in striated muscle. This pattern of expression persisted throughout the embryonic period studied. Thus, the sr-proteolipids are expressed prior to the onset of myelination and in a much broader array of cell types than their classic counterparts. These results support the conclusion that the sr-isoforms of the PLP gene have a biological role independent of myelination.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Neurônios Motores/metabolismo , Músculos/metabolismo , Proteína Proteolipídica de Mielina/genética , Animais , Imuno-Histoquímica , Camundongos , Músculos/embriologia
8.
Dev Neurosci ; 25(2-4): 96-104, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12966208

RESUMO

The myelin proteolipid gene encodes two sets of proteins, the classic PLP and DM20 and the sr (soma-restricted)-PLP and sr-DM20. Unlike the classic proteolipids, the sr-products are expressed in both neurons and oligodendrocytes (OLs) and are not components of the myelin sheath. In OLs, the sr-isoforms are associated with endosomes and recycling vesicles indicating a possible nonmyelin function for these proteins. In this study, a purified antibody specific for the sr-products was used to examine the expression of these proteins during the development of the mouse brain. We found that while sr-PLP and sr-DM20 are expressed in OLs, the highest levels of immunoreactivity were found in neuronal populations. During early embryonic development (E13-E15), sr-proteolipids were detected in the dorsal root ganglion and motor neurons in the spinal cord. By E17, immunostaining for sr-PLP and sr-DM20 in the brain increased dramatically. The highest levels of immunoreactivity were found during the first and second weeks postnatal after which staining intensity declined to adult levels and the pattern of expression was more restricted. Robust staining persisted in many neuronal populations including nuclei in the hindbrain, Purkinje and granule neurons in the cerebellum, pyramidal cells in the cortex and mitral cells in the olfactory bulb. The spatial and temporal pattern of sr-PLP and sr-DM20 expression is very similar to that of the endosomal protein, syntaxin 13, consistent with the finding that the sr-PLPs may play a role in vesicular transport in neurons.


Assuntos
Desenvolvimento Embrionário e Fetal/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteína Proteolipídica de Mielina/biossíntese , Proteína Proteolipídica de Mielina/genética , Neurônios/citologia , Animais , Encéfalo/embriologia , Embrião de Mamíferos , Feminino , Gânglios Espinais/embriologia , Imuno-Histoquímica , Camundongos , Oligodendroglia/citologia , Gravidez , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Medula Espinal/embriologia
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