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2.
Neuroscience ; 112(4): 977-91, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12088755

RESUMO

A number of signaling molecules have been implicated in the acute response to hypoxia/ischemia in the adult brain. In contrast, the reaction to chronic hypoxemia is largely unexplored. We used a protocol of chronic hypoxia in rat pups during the first three postnatal weeks, encompassing the period of cellular plasticity in the cerebral cortex. We find that the levels of fibroblast growth factor 1 (FGF1) and FGF2, two members of the FGF family, increase after 2 weeks of chronic hypoxia. In contrast, members of the neurotrophin family are unaffected. FGF2 is normally expressed in the nucleus of mature, glial fibrillary acidic protein (GFAP)-containing astrocytes. Under hypoxia, most FGF2-containing cells do not express detectable levels of GFAP, suggesting that chronic low O(2) induces their transformation into more immature glial phenotypes. Remarkably, hypoxia promotes the appearance of radial glia throughout the sub-ventricular and ependymal zones. Most of these cells express vimentin and brain lipid binding protein. A subset of these radial glial cells expresses FGF receptor 1, and are in close contact with FGF2-positive cells in the sub-ventricular zone. Thus, FGF receptor signaling in radial glia may foster cell genesis after chronic hypoxic damage. From the results of this study we suggest that after the chronic exposure to low levels of oxygen during development, the expression of radial glia increases in the forebrain periventricular region. We envision that astroglia, which are the direct descendants of radial glia, are reverting back to immature glial cells. Alternatively, hypoxia hinders the normal maturation of radial glia into GFAP-expressing astrocytes. Interestingly, hypoxia increases the levels of expression of FGF2, a factor that is essential for neuronal development. Furthermore, chronic hypoxia up-regulated FGF2's major receptor in the periventricular region. Because radial glia have been suggested to play a key role in neurogenesis and cell migration, our data suggests that hypoxia-induced FGF signaling in radial glia may represent part of a conserved program capable of regenerating neurons in the brain after injury.


Assuntos
Ventrículos Cerebrais/metabolismo , Epêndima/metabolismo , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Hipóxia/metabolismo , Neuroglia/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Western Blotting , Córtex Cerebral/metabolismo , Ventrículos Cerebrais/embriologia , Ensaio de Imunoadsorção Enzimática , Epêndima/embriologia , Imuno-Histoquímica , Ratos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Regeneração , Regulação para Cima
3.
Neuropsychopharmacology ; 25(6): 805-15, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11750175

RESUMO

The processes of stem cell proliferation and differentiation during embryogenesis are governed by transcription factors that regulate the regional differentiation of the central nervous system (CNS). Do neural "stem" cells persisting in the postnatal CNS disobey this sequence of events? The division of neural progenitor cells is promoted by basic Fibroblast Growth Factor Fgf2 or Epidermal Growth Factor Egf. However, while the intraventricular administration of FgF2 during embryogenesis increases the generation of cortical pyramidal neurons, the same treatment in the adult CNS produces interneurons of the olfactory bulb. The competence of neural progenitor cells to respond to Fgf is dictated by nuclear transcription factors that constrain neuronal fates through time. Developmentally regulated transcriptional programs are regulated by cell interactions, as dividing cells check their molecular signature against that of their environment. Thus, cell surface interactions account for competitive phenomena among pools of cells, including the inhibitory effect of neurons on the division of their progenitors, and may also explain the "permissive" effects of non-CNS environments. The challenge remains to understand the genetic programs that control the fate of progenitor cells within the postnatal CNS and their regulation by stress, apoptosis and environmental perturbations. These programs are likely to be similar to gene cascades that control proliferation, differentiation and migration of progenitor cells at earlier stages of development.


Assuntos
Sistema Nervoso/crescimento & desenvolvimento , Plasticidade Neuronal/fisiologia , Células-Tronco/fisiologia , Animais , Diferenciação Celular/fisiologia , Humanos , Regeneração Nervosa/fisiologia
4.
Brain Res Mol Brain Res ; 78(1-2): 26-37, 2000 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-10891582

RESUMO

Recent evidence implicates homeodomain-containing proteins in the specification of cell fates in the central nervous system. Here we report that in the embryonic mouse eye Otx2, a paired homeodomain transcription factor, was found in retinal pigment epithelial cells and a restricted subset of retinal neurons, including ganglion cells. In the postnatal and adult eye, however, both the cellular and subcellular distribution of the Otx2 protein were cell type-specific. Otx2 was detected only in the nuclei of retinal pigment epithelial and bipolar cells, but was present in the cytoplasm of rod photoreceptors. Immunohistochemical studies of retinal explants and transfected cell lines both suggested that the retention of Otx2 in the cytoplasm of immature rods is a developmentally regulated process. The differential distribution of Otx2 in the cytoplasm of rods and the nucleus of other cell types, suggests that subcellular localization of this transcription factor may participate cell fate determination during specific phases of retinal development.


Assuntos
Proteínas de Homeodomínio , Proteínas do Tecido Nervoso/análise , Epitélio Pigmentado Ocular/química , Células Ganglionares da Retina/química , Células Fotorreceptoras Retinianas Bastonetes/química , Transativadores/análise , Células 3T3 , Animais , Anticorpos , Western Blotting , Núcleo Celular/química , Citoplasma/química , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Camundongos Endogâmicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Fatores de Transcrição Otx , Células PC12 , Epitélio Pigmentado Ocular/citologia , Epitélio Pigmentado Ocular/embriologia , Coelhos , Ratos , Células Ganglionares da Retina/citologia , Células Fotorreceptoras Retinianas Bastonetes/citologia , Células Fotorreceptoras Retinianas Bastonetes/embriologia , Teratocarcinoma , Transativadores/genética , Transativadores/imunologia , Transfecção , Células Tumorais Cultivadas
5.
J Neurosci ; 20(13): 5012-23, 2000 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-10864959

RESUMO

Little is known about regionally specific signals that control the number of neuronal progenitor cells in vivo. We have previously shown that the germline mutation of the basic fibroblast growth factor (Fgf2) gene results in a reduction in the number of cortical neurons in the adult. We show here that Fgf2 is expressed in the pseudostratified ventricular epithelium (PVE) in a dorsoventral gradient and that Fgf2 and its receptor, Fgfr-1, are downregulated by mid to late stages of neurogenesis. In Fgf2 knockout mice, the volume and cell number of the dorsal PVE (the cerebral cortical anlage) are substantially smaller, whereas the volume of the basal PVE is unchanged. The dorsal PVE of Fgf2 knockout mice has a 50% decrease in founder cells and a reduced expansion of the progenitor pool over the first portion of neurogenesis. Despite this reduction, the degree of apoptosis within the PVE is not changed in the Fgf2 knockouts. Cortical neuron number was decreased by 45% in Fgf2 knockout mice by the end of neurogenesis, whereas the number of neurons in the basal ganglia was unaffected. Microscopically, the frontal cerebral cortex of neonatal Fgf2 null mutant mice lacked large neurons in deep cortical layers. We suggest that Fgf2 is required for the generation of a specific class of cortical neurons arising from the dorsal PVE.


Assuntos
Córtex Cerebral/embriologia , Fator 2 de Crescimento de Fibroblastos/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Receptores Proteína Tirosina Quinases/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia , Telencéfalo/embriologia , Animais , Apoptose , Divisão Celular , Plexo Corióideo/embriologia , Desenvolvimento Embrionário e Fetal , Fator 2 de Crescimento de Fibroblastos/deficiência , Fator 2 de Crescimento de Fibroblastos/genética , Mutação em Linhagem Germinativa , Idade Gestacional , Camundongos , Camundongos Knockout , Prosencéfalo/embriologia , Receptores Proteína Tirosina Quinases/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento de Fibroblastos/genética
6.
Genes Dev ; 13(21): 2787-800, 1999 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-10557207

RESUMO

Development of the neuroendocrine hypothalamus is characterized by a precise series of morphogenetic milestones culminating in terminal differentiation of neurosecretory cell lineages. The homeobox-containing gene Orthopedia (Otp) is expressed in neurons giving rise to the paraventricular (PVN), supraoptic (SON), anterior periventricular (aPV), and arcuate (ARN) nuclei throughout their development. Homozygous Otp(-/-) mice die soon after birth and display progressive impairment of crucial neuroendocrine developmental events such as reduced cell proliferation, abnormal cell migration, and failure in terminal differentiation of the parvocellular and magnocellular neurons of the aPV, PVN, SON, and ARN. Moreover, our data provide evidence that Otp and Sim1, a bHLH-PAS transcription factor that directs terminal differentiation of the PVN, SON, and aPV, act in parallel and are both required to maintain Brn2 expression which, in turn, is required for neuronal cell lineages secreting oxytocin (OT), arginine vasopressin (AVP), and corticotropin-releasing hormone (CRH).


Assuntos
Linhagem da Célula/genética , Proteínas de Homeodomínio/fisiologia , Hipotálamo/embriologia , Proteínas do Tecido Nervoso/fisiologia , Animais , Apoptose , Padronização Corporal , Divisão Celular , Feminino , Deleção de Genes , Células HeLa , Proteínas de Homeodomínio/genética , Humanos , Hipotálamo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas do Tecido Nervoso/genética
7.
Genomics ; 60(1): 96-104, 1999 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-10458915

RESUMO

Homeodomain (HD) genes are helix-turn-helix transcription factors that play key roles in the specification of cell fates. In the central nervous system (CNS), HD genes not only position cells along an axis, but also specify cell migration patterns and may influence axonal connectivity. In an effort to identify novel HD genes involved in the development of the human CNS, we have cloned, characterized, and mapped the human homologue of the murine HD gene Orthopedia (Otp), whose product is found in multiple cell groups within the mouse hypothalamus, amygdala, and brain stem. Human cDNA and genomic libraries were screened with probes derived from mouse Otp sequences to find the human homologue, OTP. The deduced amino acid sequence of the open reading frame of the human cDNA is 99% homologous to mouse Otp and demonstrates a high degree of conservation when compared to sea urchin and Drosophila. OTP was mapped to human chromosome 5q13.3 using radiation hybrid panel mapping and fluorescence in situ hybridization. Flanking markers were identified from YAC clones containing OTP. A single putative OTP gene product was found in 17-week human fetal brain tissue by Western blot analysis using a novel polyclonal antibody raised against a conserved 13-amino-acid sequence at the C-terminus of the OTP protein. Expression in the developing human hypothalamus was confirmed by immunohistochemistry.


Assuntos
Proteínas de Drosophila , Proteínas de Homeodomínio/genética , Proteínas do Tecido Nervoso/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Encéfalo/embriologia , Encéfalo/metabolismo , Bandeamento Cromossômico , Mapeamento Cromossômico , Cromossomos Humanos Par 5/genética , DNA Complementar/química , DNA Complementar/genética , Éxons , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Genes/genética , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Íntrons , Dados de Sequência Molecular , Ratos , Ratos Sprague-Dawley , Alinhamento de Sequência , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos
8.
Curr Top Dev Biol ; 46: 179-200, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10417880

RESUMO

The fibroblast growth factor (FGF) family comprises several members with distinct patterns of expression in the developing central nervous system. FGFs regulate the early specification and the subsequent growth of central nervous system regions. These different actions require the coordinated activation of distinct sets of target genes by FGFs at the appropriate stage of development. The role of FGF2 in the growth and morphogenesis of the cerebral cortex is reviewed in detail. The cellular and molecular mechanisms that underlie the action of FGF2 on cortical development are discussed.


Assuntos
Encéfalo/embriologia , Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Animais , Diferenciação Celular , Linhagem da Célula , Sistema Nervoso Central/embriologia , Córtex Cerebral/citologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Morfogênese
9.
Nat Neurosci ; 2(3): 246-53, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10195217

RESUMO

We show that fibroblast growth factor 2 (FGF2) and FGF receptors are transiently expressed by cells of the pseudostratified ventricular epithelium (PVE) during early neurogenesis. A single microinjection of FGF2 into cerebral ventricles of rat embryos at E15.5 increased the volume and total number of neurons in the adult cerebral cortex by 18% and 87%, respectively. Microinjection of FGF2 by the end of neurogenesis, at E20.5, selectively increased the number of glia. Mice lacking the FGF2 gene had fewer cortical neurons and glia at maturity. BrdU studies in FGF2-microinjected and FGF2-null animals suggested that FGF2 increases the proportion of dividing cells in the PVE without affecting the cell-cycle length. Thus, FGF2 increases the number of rounds of division of cortical progenitors.


Assuntos
Córtex Cerebral/embriologia , Fatores de Crescimento de Fibroblastos/fisiologia , Animais , Embrião de Mamíferos/anatomia & histologia , Embrião de Mamíferos/citologia , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário e Fetal/fisiologia , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Camundongos , Camundongos Knockout/genética , Microinjeções , Ratos/embriologia , Células-Tronco/fisiologia
10.
J Mol Neurosci ; 8(2): 93-113, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9188040

RESUMO

Homeodomain-containing genes of the Dlx family are expressed in the developing basal ganglia. To investigate the role of Dlx genes during development, we studied their cellular localization in primary cultures of embryonic basal telencephalon, and examined the changes in cellular phenotypes resulting from blockade of Dlx-2 expression. Cells containing Dlx-1, Dlx-2, and Dlx-5 mRNAs are immature cells of the neuronal lineage expressing the microtubule-associated proteins (MAPs) MAP1B and MAP2, but not glial fibrillary acidic protein (GFAP). Treatment of these cells with antisense oligonucleotides targeted to Dlx-2 caused a specific decrease of Dlx-2 mRNA and protein. This decrease in the Dlx-2 gene product was associated with a decrease in the expression of MAP2, a protein localized in neuronal dendrites, along with a smaller decrease in the 200-kDa neurofilament subunit (NF-H). Proteins expressed preferentially in axons were unchanged. This reduction in MAP2 expression was associated with a decrease in dendrite outgrowth and an increased level of cell proliferation. None of these changes were elicited by antisense oligonucleotides targeted to Dlx-1. We suggest that the Dlx-2 gene product regulates two interrelated aspects of neuronal differentiation: the exit from the mitotic cycle and the capability to grow MAP2-positive dendrites. As such, this gene product may be important for the establishment of neuronal polarity, setting the stage for afferent synaptic connectivity.


Assuntos
Gânglios da Base/citologia , Proteínas de Ligação a DNA/genética , Genes Homeobox/fisiologia , Proteínas de Homeodomínio , Neurônios/citologia , Animais , Especificidade de Anticorpos , Elementos Antissenso (Genética) , Gânglios da Base/química , Diferenciação Celular/genética , Divisão Celular/fisiologia , Células Cultivadas , Proteínas do Citoesqueleto , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hibridização In Situ , Proteínas Associadas aos Microtúbulos/análise , Proteínas Associadas aos Microtúbulos/imunologia , Neuritos/química , Neuritos/fisiologia , Neurônios/fisiologia , Neurônios/ultraestrutura , Fenótipo , Gravidez , Proteínas de Ligação a RNA , Ratos , Rombencéfalo/química , Rombencéfalo/citologia , Telencéfalo/química , Telencéfalo/citologia , Fatores de Transcrição
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