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2.
Elife ; 72018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29676260

RESUMO

Most neurogenesis in the mammalian brain is completed embryonically, but in certain areas the production of neurons continues throughout postnatal life. The functional properties of mature postnatally generated neurons often match those of their embryonically produced counterparts. However, we show here that in the olfactory bulb (OB), embryonic and postnatal neurogenesis produce functionally distinct subpopulations of dopaminergic (DA) neurons. We define two subclasses of OB DA neuron by the presence or absence of a key subcellular specialisation: the axon initial segment (AIS). Large AIS-positive axon-bearing DA neurons are exclusively produced during early embryonic stages, leaving small anaxonic AIS-negative cells as the only DA subtype generated via adult neurogenesis. These populations are functionally distinct: large DA cells are more excitable, yet display weaker and - for certain long-latency or inhibitory events - more broadly tuned responses to odorant stimuli. Embryonic and postnatal neurogenesis can therefore generate distinct neuronal subclasses, placing important constraints on the functional roles of adult-born neurons in sensory processing.


Assuntos
Segmento Inicial do Axônio/classificação , Neurônios Dopaminérgicos/classificação , Neurônios Dopaminérgicos/citologia , Neurogênese , Bulbo Olfatório/embriologia , Animais , Camundongos Endogâmicos C57BL , Fenótipo
3.
Neuron ; 96(4): 871-882.e5, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29107520

RESUMO

Synaptic scaling is a key homeostatic plasticity mechanism and is thought to be involved in the regulation of cortical activity levels. Here we investigated the spatial scale of homeostatic changes in spine size following sensory deprivation in a subset of inhibitory (layer 2/3 GAD65-positive) and excitatory (layer 5 Thy1-positive) neurons in mouse visual cortex. Using repeated in vivo two-photon imaging, we find that increases in spine size are tumor necrosis factor alpha (TNF-α) dependent and thus are likely associated with synaptic scaling. Rather than occurring at all spines, the observed increases in spine size are spatially localized to a subset of dendritic branches and are correlated with the degree of recent local spine loss within that branch. Using simulations, we show that such a compartmentalized form of synaptic scaling has computational benefits over cell-wide scaling for information processing within the cell.


Assuntos
Dendritos/fisiologia , Espinhas Dendríticas/fisiologia , Plasticidade Neuronal/fisiologia , Privação Sensorial/fisiologia , Animais , Simulação por Computador , Feminino , Homeostase/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Córtex Visual/fisiologia
4.
Elife ; 42015 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-25556700

RESUMO

miR-128, a brain-enriched microRNA, has been implicated in the control of neurogenesis and synaptogenesis but its potential roles in intervening processes have not been addressed. We show that post-transcriptional mechanisms restrict miR-128 accumulation to post-mitotic neurons during mouse corticogenesis and in adult stem cell niches. Whereas premature miR-128 expression in progenitors for upper layer neurons leads to impaired neuronal migration and inappropriate branching, sponge-mediated inhibition results in overmigration. Within the upper layers, premature miR-128 expression reduces the complexity of dendritic arborization, associated with altered electrophysiological properties. We show that Phf6, a gene mutated in the cognitive disorder Börjeson-Forssman-Lehmann syndrome, is an important regulatory target for miR-128. Restoring PHF6 expression counteracts the deleterious effect of miR-128 on neuronal migration, outgrowth and intrinsic physiological properties. Our results place miR-128 upstream of PHF6 in a pathway vital for cortical lamination as well as for the development of neuronal morphology and intrinsic excitability.


Assuntos
Movimento Celular , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , MicroRNAs/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Envelhecimento/metabolismo , Animais , Forma Celular , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Dendritos/metabolismo , Epilepsia/genética , Face/anormalidades , Dedos/anormalidades , Regulação da Expressão Gênica no Desenvolvimento , Transtornos do Crescimento/genética , Proteínas de Homeodomínio/metabolismo , Hipogonadismo/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Camundongos , MicroRNAs/genética , Obesidade/genética , Precursores de RNA/metabolismo , Proteínas Repressoras , Nicho de Células-Tronco , Fatores de Tempo , Transcrição Gênica
5.
PLoS One ; 7(5): e37767, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22666391

RESUMO

Toll-like receptors (TLR) are key players of the innate and adaptive immune response in vertebrates. The original protein Toll in Drosophila melanogaster regulates both host defense and morphogenesis during development. Making use of real-time PCR, in situ hybridization, and immunohistochemistry we systematically examined the expression of TLR1-9 and the intracellular adaptor molecules MyD88 and TRIF during development of the mouse brain. Expression of TLR7 and TLR9 in the brain was strongly regulated during different embryonic, postnatal, and adult stages. In contrast, expression of TLR1-6, TLR8, MyD88, and TRIF mRNA displayed no significant changes in the different phases of brain development. Neurons of various brain regions including the neocortex and the hippocampus were identified as the main cell type expressing both TLR7 and TLR9 in the developing brain. Taken together, our data reveal specific expression patterns of distinct TLRs in the developing mouse brain and lay the foundation for further investigation of the pathophysiological significance of these receptors for developmental processes in the central nervous system of vertebrates.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Transcriptoma , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Axônios/metabolismo , Encéfalo/citologia , Células HEK293 , Humanos , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
6.
Nat Neurosci ; 15(6): 827-35, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22610069

RESUMO

Activation of innate immune receptors by host-derived factors exacerbates CNS damage, but the identity of these factors remains elusive. We uncovered an unconventional role for the microRNA let-7, a highly abundant regulator of gene expression in the CNS, in which extracellular let-7 activates the RNA-sensing Toll-like receptor (TLR) 7 and induces neurodegeneration through neuronal TLR7. Cerebrospinal fluid (CSF) from individuals with Alzheimer's disease contains increased amounts of let-7b, and extracellular introduction of let-7b into the CSF of wild-type mice by intrathecal injection resulted in neurodegeneration. Mice lacking TLR7 were resistant to this neurodegenerative effect, but this susceptibility to let-7 was restored in neurons transfected with TLR7 by intrauterine electroporation of Tlr7(−/−) fetuses. Our results suggest that microRNAs can function as signaling molecules and identify TLR7 as an essential element in a pathway that contributes to the spread of CNS damage.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Glicoproteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Degeneração Neural/metabolismo , Neurônios/metabolismo , Receptor 7 Toll-Like/metabolismo , Doença de Alzheimer/genética , Animais , Apoptose/fisiologia , Encéfalo/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Células HEK293 , Humanos , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/fisiologia
7.
Adv Exp Med Biol ; 700: 85-105, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21755476

RESUMO

Trim-NHL proteins are defined by RING, B-Box and Coiled-coil protein motifs (referred to collectively as the Trim domain) coupled to an NHL domain. The C. elegans, D. melanogaster, mouse and human Trim-NHL proteins are potential and in several cases confirmed, E3 ubiquitin ligases. Current research is focused on identifying targets and pathways for Trim-NHL-mediated ubiquitination and in assessing the contribution of the NHL protein-protein interaction domain for function and specificity. Several Trim-NHL proteins were discovered in screens for developmental genes in model organisms; mutations in one of the family members, Trim32, cause developmental disturbances in humans. In most instances, mutations that alter protein function map to the NHL domain. The NHL domain is a scaffold for the assembly of a translational repressor complex by the Brat proto-oncogene, a well-studied family member in Drosophila. The link to translational control is common to at least four Trim-NHLs that associate with miRNA pathway proteins. So far, two have been shown to repress (Mei-P26 and Lin41) and two to promote (NHL-2, Trim32) miRNA-mediated gene silencing. In this chapter we will describe structure-function relations for each of the proteins and then focus on the lessons being learned from these proteins about miRNA functions in development and in stem cell biology.


Assuntos
Drosophila melanogaster , MicroRNAs , Animais , Caenorhabditis elegans/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Humanos , MicroRNAs/metabolismo , Proto-Oncogene Mas , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
8.
Adv Exp Med Biol ; 700: 85-105, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21627033

RESUMO

Trim-NHL proteins are defined by RING, B-Box and Coiled-coil protein motifs (referred to collectively as the Trim domain) coupled to an NHL domain. The C. elegans, D. melanogaster, mouse and human Trim-NHL proteins are potential and in several cases confirmed, E3 ubiquitin ligases. Current research is focused on identifying targets and pathways for Trim-NHL-mediated ubiquitination and in assessing the contribution of the NHL protein-protein interactiondomain for function and specificity. Several Trim-NHL proteins were discovered in screens for developmental genes in model organisms; mutations in one of the family members, Trim32, cause developmental disturbances in humans. In most instances, mutations that alter protein function map to the NHL domain. The NHL domain is a scaffold for the assembly of a translational repressor complex by the Brat proto-oncogene, a well-studied family member in Drosophila. The link to translational control is common to at least four Trim-NHLs that associate with miRNA pathway proteins. So far, two have been shown to repress (Mei-P26 and Lin41) and two to promote (NHL-2, Trim32) miRNA-mediated gene silencing. In this chapter we will describe structure-function relations for each of the proteins and then focus on the lessons being learned from these proteins about miRNA functions in development and in stem cell biology.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas de Membrana/fisiologia , MicroRNAs/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/química , Animais , Proteínas de Caenorhabditis elegans/fisiologia , Proteínas de Transporte/fisiologia , Proteínas de Drosophila/fisiologia , Humanos , Proteínas de Membrana/química , Estrutura Terciária de Proteína , Proto-Oncogene Mas , Fatores de Transcrição/fisiologia , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Ubiquitinação
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