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1.
Genes Dev ; 27(16): 1769-86, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23964093

RESUMO

The majority of neural stem cells (NSCs) in the adult brain are quiescent, and this fraction increases with aging. Although signaling pathways that promote NSC quiescence have been identified, the transcriptional mechanisms involved are mostly unknown, largely due to lack of a cell culture model. In this study, we first demonstrate that NSC cultures (NS cells) exposed to BMP4 acquire cellular and transcriptional characteristics of quiescent cells. We then use epigenomic profiling to identify enhancers associated with the quiescent NS cell state. Motif enrichment analysis of these enhancers predicts a major role for the nuclear factor one (NFI) family in the gene regulatory network controlling NS cell quiescence. Interestingly, we found that the family member NFIX is robustly induced when NS cells enter quiescence. Using genome-wide location analysis and overexpression and silencing experiments, we demonstrate that NFIX has a major role in the induction of quiescence in cultured NSCs. Transcript profiling of NS cells overexpressing or silenced for Nfix and the phenotypic analysis of the hippocampus of Nfix mutant mice suggest that NFIX controls the quiescent state by regulating the interactions of NSCs with their microenvironment.


Assuntos
Epigênese Genética , Fatores de Transcrição NFI/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Animais , Proteína Morfogenética Óssea 4/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Células HEK293 , Humanos , Camundongos , Fatores de Transcrição NFI/genética , Células-Tronco Neurais/efeitos dos fármacos , Ligação Proteica
2.
Cereb Cortex ; 25(10): 3758-78, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25331604

RESUMO

Transcription factors of the nuclear factor one (NFI) family play a pivotal role in the development of the nervous system. One member, NFIX, regulates the development of the neocortex, hippocampus, and cerebellum. Postnatal Nfix(-/-) mice also display abnormalities within the subventricular zone (SVZ) lining the lateral ventricles, a region of the brain comprising a neurogenic niche that provides ongoing neurogenesis throughout life. Specifically, Nfix(-/-) mice exhibit more PAX6-expressing progenitor cells within the SVZ. However, the mechanism underlying the development of this phenotype remains undefined. Here, we reveal that NFIX contributes to multiple facets of SVZ development. Postnatal Nfix(-/-) mice exhibit increased levels of proliferation within the SVZ, both in vivo and in vitro as assessed by a neurosphere assay. Furthermore, we show that the migration of SVZ-derived neuroblasts to the olfactory bulb is impaired, and that the olfactory bulbs of postnatal Nfix(-/-) mice are smaller. We also demonstrate that gliogenesis within the rostral migratory stream is delayed in the absence of Nfix, and reveal that Gdnf (glial-derived neurotrophic factor), a known attractant for SVZ-derived neuroblasts, is a target for transcriptional activation by NFIX. Collectively, these findings suggest that NFIX regulates both proliferation and migration during the development of the SVZ neurogenic niche.


Assuntos
Movimento Celular , Proliferação de Células , Ventrículos Laterais/embriologia , Fatores de Transcrição NFI/fisiologia , Células-Tronco Neurais/fisiologia , Neurogênese , Animais , Feminino , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Interneurônios/fisiologia , Ventrículos Laterais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Transcrição NFI/genética , Fatores de Transcrição NFI/metabolismo , Neuroglia/fisiologia , Bulbo Olfatório/embriologia , Bulbo Olfatório/metabolismo , Nicho de Células-Tronco
3.
Cereb Cortex ; 23(8): 1811-23, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22710612

RESUMO

Deletion of LIM homeodomain transcription factor-encoding Lhx6 gene in mice results in defective tangential migration of cortical interneurons and failure of differentiation of the somatostatin (Sst)- and parvalbumin (Pva)-expressing subtypes. Here, we characterize a novel hypomorphic allele of Lhx6 and demonstrate that reduced activity of this locus leads to widespread differentiation defects in Sst(+) interneurons, but relatively minor and localized changes in Pva(+) interneurons. The reduction in the number of Sst-expressing cells was not associated with a loss of interneurons, because the migration and number of Lhx6-expressing interneurons and expression of characteristic molecular markers, such as calretinin or Neuropeptide Y, were not affected in Lhx6 hypomorphic mice. Consistent with a selective deficit in the differentiation of Sst(+) interneurons in the CA1 subfield of the hippocampus, we observed reduced expression of metabotropic Glutamate Receptor 1 in the stratum oriens and characteristic changes in dendritic inhibition, but normal inhibitory input onto the somatic compartment of CA1 pyramidal cells. Moreover, Lhx6 hypomorphs show behavioral, histological, and electroencephalographic signs of recurrent seizure activity, starting from early adulthood. These results demonstrate that Lhx6 plays an important role in the maturation of cortical interneurons and the formation of inhibitory circuits in the mammalian cortex.


Assuntos
Córtex Cerebral/fisiologia , Interneurônios/fisiologia , Proteínas com Homeodomínio LIM/fisiologia , Rede Nervosa/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Fatores de Transcrição/fisiologia , Animais , Movimento Celular/fisiologia , Córtex Cerebral/crescimento & desenvolvimento , Interneurônios/citologia , Proteínas com Homeodomínio LIM/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética
4.
Neuron ; 83(5): 1085-97, 2014 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-25189209

RESUMO

The activity of adult stem cells is regulated by signals emanating from the surrounding tissue. Many niche signals have been identified, but it is unclear how they influence the choice of stem cells to remain quiescent or divide. Here we show that when stem cells of the adult hippocampus receive activating signals, they first induce the expression of the transcription factor Ascl1 and only subsequently exit quiescence. Moreover, lowering Ascl1 expression reduces the proliferation rate of hippocampal stem cells, and inactivating Ascl1 blocks quiescence exit completely, rendering them unresponsive to activating stimuli. Ascl1 promotes the proliferation of hippocampal stem cells by directly regulating the expression of cell-cycle regulatory genes. Ascl1 is similarly required for stem cell activation in the adult subventricular zone. Our results support a model whereby Ascl1 integrates inputs from both stimulatory and inhibitory signals and converts them into a transcriptional program activating adult neural stem cells.


Assuntos
Células-Tronco Adultas/citologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Hipocampo/citologia , Neurogênese/genética , Células-Tronco Adultas/metabolismo , Fatores Etários , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proliferação de Células , Ventrículos Cerebrais/citologia , Transportador 1 de Aminoácido Excitatório/genética , Transportador 1 de Aminoácido Excitatório/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/deficiência , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Ácido Caínico/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas com Domínio T/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
5.
Cell Rep ; 2(5): 1351-62, 2012 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-23142661

RESUMO

The generation of cortical interneuron subtypes is controlled by genetic programs that are activated in the ventral forebrain and unfold during the prolonged period of inhibitory neuron development. The LIM-homeodomain protein LHX6 is critical for the development of all cortical interneurons originating in the medial ganglionic eminence, but the molecular mechanisms that operate downstream of LHX6 to control the terminal differentiation of somatostatin- and parvalbumin-expressing interneurons within the cortex remain unknown. Here, we provide evidence that the nuclear matrix and genome organizer protein SATB1 is induced by neuronal activity and functions downstream of Lhx6 to control the transition of tangentially migrating immature interneurons into the terminally differentiated Somatostatin (SST)-expressing subtype. Our experiments provide a molecular framework for understanding the genetic and epigenetic mechanisms by which specified but immature cortical interneurons acquire the subtype-defining molecular and morphophysiological characteristics that allow them to integrate and function within cortical circuits.


Assuntos
Córtex Cerebral/citologia , Interneurônios/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Córtex Cerebral/embriologia , Córtex Cerebral/metabolismo , Embrião de Mamíferos/metabolismo , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Perfilação da Expressão Gênica , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Proteínas com Homeodomínio LIM/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/antagonistas & inibidores , Proteínas de Ligação à Região de Interação com a Matriz/genética , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Somatostatina/metabolismo , Fatores de Transcrição/metabolismo
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