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1.
Life Sci Alliance ; 5(12)2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36150742

RESUMO

Homeostatic synaptic depression (HSD) in excitatory neurons is a cell-autonomous mechanism which protects excitatory neurons from over-excitation as a consequence of chronic increases in network activity. In this process, excitatory synapses are weakened and eventually eliminated, as evidenced by a reduction in synaptic AMPA receptor expression and dendritic spine loss. Originally considered a global, cell-wide mechanism, local forms of regulation, such as the local control of mRNA translation in dendrites, are being increasingly recognized in HSD. Yet, identification of excitatory proteins whose local regulation is required for HSD is still limited. Here, we show that proline-rich protein 7/transmembrane adapter protein 3 (Prr7) down-regulation in dendrites of rat hippocampal neurons is necessary for HSD induced by chronic increase in network activity resulting from a blockade of inhibitory synaptic transmission by picrotoxin (PTX). We further identify two activity-regulated miRNAs, miR-329-3p and miR-495-3p, which inhibit Prr7 mRNA translation and are required for HSD. Moreover, we found that Prr7 knockdown reduces expression of the synaptic scaffolding protein SPAR, which is rescued by pharmacological inhibition of CDK5, indicating a role of Prr7 protein in the maintenance of excitatory synapses via protection of SPAR from degradation. Together, our findings highlight a novel HSD mechanism in which chronic activity leads to miR-329- and miR-495-mediated Prr7 reduction upstream of the CDK5-SPAR pathway.


Assuntos
Depressão Sináptica de Longo Prazo , Proteínas de Membrana , MicroRNAs , Proteínas do Tecido Nervoso , Neurônios , Animais , Regulação para Baixo , Hipocampo/citologia , Proteínas de Membrana/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Picrotoxina/farmacologia , Ratos , Receptores de AMPA/metabolismo
2.
Genes Dev ; 32(1): 26-41, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29378787

RESUMO

Regulation by gene-distal enhancers is critical for cell type-specific and condition-specific patterns of gene expression. Thus, to understand the basis of gene activity in a given cell type or tissue, we must identify the precise locations of enhancers and functionally characterize their behaviors. Here, we demonstrate that transcription is a nearly universal feature of enhancers in Drosophila and mammalian cells and that nascent RNA sequencing strategies are optimal for identification of both enhancers and superenhancers. We dissect the mechanisms governing enhancer transcription and discover remarkable similarities to transcription at protein-coding genes. We show that RNA polymerase II (RNAPII) undergoes regulated pausing and release at enhancers. However, as compared with mRNA genes, RNAPII at enhancers is less stable and more prone to early termination. Furthermore, we found that the level of histone H3 Lys4 (H3K4) methylation at enhancers corresponds to transcriptional activity such that highly active enhancers display H3K4 trimethylation rather than the H3K4 monomethylation considered a hallmark of enhancers. Finally, our work provides insights into the unique characteristics of superenhancers, which stimulate high-level gene expression through rapid pause release; interestingly, this property renders associated genes resistant to the loss of factors that stabilize paused RNAPII.


Assuntos
Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Elongação da Transcrição Genética , Animais , Cromatina/química , Proteínas Cromossômicas não Histona/fisiologia , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/biossíntese , Proteínas de Drosophila/fisiologia , Células-Tronco Embrionárias/metabolismo , Histonas/metabolismo , Camundongos , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , RNA não Traduzido/biossíntese , Sítio de Iniciação de Transcrição , Transcrição Gênica , Fatores de Elongação da Transcrição/fisiologia
3.
CNS Neurol Disord Drug Targets ; 15(5): 544-50, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27071793

RESUMO

Rett syndrome (RTT) is one of a group of neurodevelopmental disorders typically characterized by deficits in the X-linked gene MECP2 (methyl-CpG binding protein 2). The MECP2 gene encodes a multifunctional protein involved in transcriptional repression, transcriptional activation, chromatin remodeling, and RNA splicing. Genetic deletion of Mecp2 in mice revealed neuronal disabilities including RTT-like phenotypes and provided an excellent platform for understanding the pathogenesis of RTT. So far, there are no effective pharmacological treatments for RTT because the role of MECP2 in RTT is incompletely understood. Recently, human induced pluripotent stem cell (hiPSC) technologies have improved our knowledge of neurological and neurodevelopmental diseases including RTT because neurons derived from RTT-hiPSCs can be used for disease modeling to understand RTT phenotypes and to perform high throughput pharmaceutical drug screening. In this review, we provide an overview of RTT, including MeCP2 function and mouse models of RTT. In addition, we introduce recent advances in disease modeling of RTT using hiPSC-derived neural cells.


Assuntos
Células-Tronco Pluripotentes Induzidas/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Neurônios/metabolismo , Síndrome de Rett/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Camundongos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Síndrome de Rett/tratamento farmacológico
4.
Microscopy (Oxf) ; 64(1): 57-67, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25527636

RESUMO

The aim of connectomics analysis is to understand whole-brain neural connections. This is accomplished using new biotechnologies. Here, we provide an overview of the recent progress in connectomics analysis. The entire neural network of an organism was revealed for the first time in the nematode. Caenorhabditis elegans (C. elegans) have an advantage of their limited number of neurons and their transparency, allowing the neural network to be visualized using light and electron microscopes (EMs). It is practically impossible to adopt the same approach for mammals because of the large number of neural cells and the opacity of the central nervous system. A variety of new technologies are being developed to perform computer-assisted high-throughput image acquisition and analysis to obtain whole-brain maps for higher species, including mammals. Diffusion tensor magnetic resonance imaging and tractography and three-dimensional imaging with the EM are examples of novel approaches to connectomics. These new technologies will soon be applied not only to Drosophila, C. elegans and rodent research, but also to comprehensive connectomics analysis in a wide range of species including humans and primates. In the near future, results from connectomics analysis will reveal the neural circuitry of the whole brain and enhance our understanding of the human mind and neuropsychiatric diseases.


Assuntos
Encéfalo/ultraestrutura , Conectoma/métodos , Animais , Caenorhabditis elegans/ultraestrutura , Imagem de Difusão por Ressonância Magnética/métodos , Drosophila/ultraestrutura , Genômica/métodos , Humanos , Imageamento Tridimensional/métodos , Redes Neurais de Computação , Neurônios/ultraestrutura
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