Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Mol Cell ; 84(4): 621-639.e9, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38244545

RESUMEN

The DNA-binding protein SATB2 is genetically linked to human intelligence. We studied its influence on the three-dimensional (3D) epigenome by mapping chromatin interactions and accessibility in control versus SATB2-deficient cortical neurons. We find that SATB2 affects the chromatin looping between enhancers and promoters of neuronal-activity-regulated genes, thus influencing their expression. It also alters A/B compartments, topologically associating domains, and frequently interacting regions. Genes linked to SATB2-dependent 3D genome changes are implicated in highly specialized neuronal functions and contribute to cognitive ability and risk for neuropsychiatric and neurodevelopmental disorders. Non-coding DNA regions with a SATB2-dependent structure are enriched for common variants associated with educational attainment, intelligence, and schizophrenia. Our data establish SATB2 as a cell-type-specific 3D genome modulator, which operates both independently and in cooperation with CCCTC-binding factor (CTCF) to set up the chromatin landscape of pyramidal neurons for cognitive processes.


Asunto(s)
Proteínas de Unión a la Región de Fijación a la Matriz , Factores de Transcripción , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neuronas/metabolismo , Factor de Unión a CCCTC/metabolismo , Cromatina/genética , Cromatina/metabolismo , Genoma , Cognición , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo
2.
Nature ; 599(7886): 684-691, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34789882

RESUMEN

The three-dimensional (3D) structure of chromatin is intrinsically associated with gene regulation and cell function1-3. Methods based on chromatin conformation capture have mapped chromatin structures in neuronal systems such as in vitro differentiated neurons, neurons isolated through fluorescence-activated cell sorting from cortical tissues pooled from different animals and from dissociated whole hippocampi4-6. However, changes in chromatin organization captured by imaging, such as the relocation of Bdnf away from the nuclear periphery after activation7, are invisible with such approaches8. Here we developed immunoGAM, an extension of genome architecture mapping (GAM)2,9, to map 3D chromatin topology genome-wide in specific brain cell types, without tissue disruption, from single animals. GAM is a ligation-free technology that maps genome topology by sequencing the DNA content from thin (about 220 nm) nuclear cryosections. Chromatin interactions are identified from the increased probability of co-segregation of contacting loci across a collection of nuclear slices. ImmunoGAM expands the scope of GAM to enable the selection of specific cell types using low cell numbers (approximately 1,000 cells) within a complex tissue and avoids tissue dissociation2,10. We report cell-type specialized 3D chromatin structures at multiple genomic scales that relate to patterns of gene expression. We discover extensive 'melting' of long genes when they are highly expressed and/or have high chromatin accessibility. The contacts most specific of neuron subtypes contain genes associated with specialized processes, such as addiction and synaptic plasticity, which harbour putative binding sites for neuronal transcription factors within accessible chromatin regions. Moreover, sensory receptor genes are preferentially found in heterochromatic compartments in brain cells, which establish strong contacts across tens of megabases. Our results demonstrate that highly specific chromatin conformations in brain cells are tightly related to gene regulation mechanisms and specialized functions.


Asunto(s)
Encéfalo/citología , Células/clasificación , Ensamble y Desensamble de Cromatina , Cromatina/química , Cromatina/genética , Genes , Conformación Molecular , Animales , Sitios de Unión , Células/metabolismo , Cromatina/metabolismo , Regulación de la Expresión Génica , Masculino , Ratones , Familia de Multigenes/genética , Neuronas/clasificación , Neuronas/metabolismo , Desnaturalización de Ácido Nucleico , Factores de Transcripción/metabolismo
3.
EMBO J ; 40(3): e103701, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33319920

RESUMEN

SATB2 is a schizophrenia risk gene and is genetically associated with human intelligence. How it affects cognition at molecular level is currently unknown. Here, we show that interactions between SATB2, a chromosomal scaffolding protein, and the inner nuclear membrane protein LEMD2 orchestrate the response of pyramidal neurons to neuronal activation. Exposure to novel environment in vivo causes changes in nuclear shape of CA1 hippocampal neurons via a SATB2-dependent mechanism. The activity-driven plasticity of the nuclear envelope requires not only SATB2, but also its protein interactor LEMD2 and the ESCRT-III/VPS4 membrane-remodeling complex. Furthermore, LEMD2 depletion in cortical neurons, similar to SATB2 ablation, affects neuronal activity-dependent regulation of multiple rapid and delayed primary response genes. In human genetic data, LEMD2-regulated genes are enriched for de novo mutations reported in intellectual disability and schizophrenia and are, like SATB2-regulated genes, enriched for common variants associated with schizophrenia and cognitive function. Hence, interactions between SATB2 and the inner nuclear membrane protein LEMD2 influence gene expression programs in pyramidal neurons that are linked to cognitive ability and psychiatric disorder etiology.


Asunto(s)
Redes Reguladoras de Genes , Hipocampo/citología , Discapacidad Intelectual/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Proteínas de la Membrana/metabolismo , Mutación , Proteínas Nucleares/metabolismo , Esquizofrenia/genética , Factores de Transcripción/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Animales , Núcleo Celular/metabolismo , Plasticidad de la Célula , Células Cultivadas , Cognición , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Células HeLa , Hipocampo/metabolismo , Humanos , Discapacidad Intelectual/metabolismo , Masculino , Proteínas de Unión a la Región de Fijación a la Matriz/química , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Ratones , Neuronas/citología , Neuronas/metabolismo , Membrana Nuclear/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/genética , Esquizofrenia/metabolismo , Factores de Transcripción/química , Factores de Transcripción/genética , ATPasas de Translocación de Protón Vacuolares/metabolismo
4.
PLoS Genet ; 15(2): e1007890, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30726206

RESUMEN

During CNS development, the nuclear protein SATB2 is expressed in superficial cortical layers and determines projection neuron identity. In the adult CNS, SATB2 is expressed in pyramidal neurons of all cortical layers and is a regulator of synaptic plasticity and long-term memory. Common variation in SATB2 locus confers risk of schizophrenia, whereas rare, de novo structural and single nucleotide variants cause severe intellectual disability and absent or limited speech. To characterize differences in SATB2 molecular function in developing vs adult neocortex, we isolated SATB2 protein interactomes at the two ontogenetic stages and identified multiple novel SATB2 interactors. SATB2 interactomes are highly enriched for proteins that stabilize de novo chromatin loops. The comparison between the neonatal and adult SATB2 protein complexes indicates a developmental shift in SATB2 molecular function, from transcriptional repression towards organization of chromosomal superstructure. Accordingly, gene sets regulated by SATB2 in the neocortex of neonatal and adult mice show limited overlap. Genes encoding SATB2 protein interactors were grouped for gene set analysis of human GWAS data. Common variants associated with human cognitive ability are enriched within the genes encoding adult but not neonatal SATB2 interactors. Our data support a shift in the function of SATB2 in cortex over lifetime and indicate that regulation of spatial chromatin architecture by the SATB2 interactome contributes to cognitive function in the general population.


Asunto(s)
Cognición/fisiología , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Neocórtex/fisiología , Factores de Transcripción/genética , Adulto , Animales , Humanos , Memoria a Largo Plazo/fisiología , Ratones , Ratones Endogámicos C57BL , Neuronas/fisiología , Polimorfismo de Nucleótido Simple/genética , Transcripción Genética/genética
5.
Addict Biol ; 26(1): e12878, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-31984611

RESUMEN

Social interaction in an alternative context can be beneficial against drugs of abuse. Stress is known to be a risk factor that can exacerbate the effects of addictive drugs. In this study, we investigated whether the positive effects of social interaction are mediated through a decrease in stress levels. For that purpose, rats were trained to express cocaine or social interaction conditioned place preference (CPP). Behavioural, hormonal, and molecular stress markers were evaluated. We found that social CPP decreased the percentage of incorrect transitions of grooming and corticosterone to the level of naïve untreated rats. In addition, corticotropin-releasing factor (CRF) was increased in the bed nucleus of stria terminalis after cocaine CPP. In order to study the modulation of social CPP by the CRF system, rats received intracerebroventricular CRF or alpha-helical CRF, a nonselective antagonist of CRF receptors. The subsequent effects on CPP to cocaine or social interaction were observed. CRF injections increased cocaine CPP, whereas alpha-helical CRF injections decreased cocaine CPP. However, alpha-helical CRF injections potentiated social CPP. When social interaction was made available in an alternative context, CRF-induced increase of cocaine preference was reversed completely to the level of rats receiving cocaine paired with alpha-helical CRF. This reversal of cocaine preference was also paralleled by a reversal in CRF-induced increase of p38 MAPK expression in the nucleus accumbens shell. These findings suggest that social interaction could contribute as a valuable component in treatment of substance use disorders by reducing stress levels.


Asunto(s)
Recompensa , Interacción Social , Estrés Psicológico/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Cocaína/farmacología , Condicionamiento Clásico/efectos de los fármacos , Hormona Liberadora de Corticotropina/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Masculino , Núcleo Accumbens/efectos de los fármacos , Ratas , Receptores de Hormona Liberadora de Corticotropina/metabolismo
6.
PLoS Genet ; 14(7): e1007515, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-30040823

RESUMEN

SATB2 is associated with schizophrenia and is an important transcription factor regulating neocortical organization and circuitry. Rare mutations in SATB2 cause a syndrome that includes developmental delay, and mouse studies identify an important role for SATB2 in learning and memory. Interacting partners BCL11B and GATAD2A are also schizophrenia risk genes indicating that other genes interacting with or are regulated by SATB2 are making a contribution to schizophrenia and cognition. We used data from Satb2 mouse models to generate three gene-sets that contain genes either functionally related to SATB2 or targeted by SATB2 at different stages of development. Each was tested for enrichment using the largest available genome-wide association studies (GWAS) datasets for schizophrenia and educational attainment (EA) and enrichment analysis was also performed for schizophrenia and other neurodevelopmental disorders using data from rare variant sequencing studies. These SATB2 gene-sets were enriched for genes containing common variants associated with schizophrenia and EA, and were enriched for genes containing rare variants reported in studies of schizophrenia, autism and intellectual disability. In the developing cortex, genes targeted by SATB2 based on ChIP-seq data, and functionally affected when SATB2 is not expressed based on differential expression analysis using RNA-seq data, show strong enrichment for genes associated with EA. For genes expressed in the hippocampus or at the synapse, those targeted by SATB2 are more strongly enriched for genes associated EA than gene-sets not targeted by SATB2. This study demonstrates that single gene findings from GWAS can provide important insights to pathobiological processes. In this case we find evidence that genes influenced by SATB2 and involved in synaptic transmission, axon guidance and formation of the corpus callosum are contributing to schizophrenia and cognition.


Asunto(s)
Cognición , Regulación del Desarrollo de la Expresión Génica , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Trastornos del Neurodesarrollo/genética , Esquizofrenia/genética , Factores de Transcripción/metabolismo , Éxito Académico , Animales , Orientación del Axón/genética , Cuerpo Calloso/crecimiento & desarrollo , Cuerpo Calloso/metabolismo , Conjuntos de Datos como Asunto , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Genómica/métodos , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Humanos , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Ratones , Mutación , Trastornos del Neurodesarrollo/patología , Esquizofrenia/patología , Transmisión Sináptica/genética , Factores de Transcripción/genética
7.
Int J Mol Sci ; 22(1)2020 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-33396297

RESUMEN

Evidence suggests that PKA activity in the nucleus accumbens (NAc) plays an essential role in reward-related learning. In this study, we investigated whether PKA is differentially involved in the expression of learning produced by either natural reinforcers or psychostimulants. For that purpose, we inhibited PKA through a bilateral infusion of Rp-cAMPS, a specific PKA inhibitor, directly into the NAc. The effects of PKA inhibition in the NAc on the expression of concurrent conditioned place preference (CPP) for cocaine (drug) and social interaction (natural reward) in rats were evaluated. We found that PKA inhibition increased the expression of cocaine preference. This effect was not due to altered stress levels or decreased social reward. PKA inhibition did not affect the expression of natural reward as intra-NAc Rp-cAMPS infusion did not affect expression of social preference. When rats were trained to express cocaine or social interaction CPP and tested for eventual persisting preference 7 and 14 days after CPP expression, cocaine preference was persistent, but social preference was abolished after the first test. These results suggest that PKA in the NAc is involved in drug reward learning that might lead to addiction and that only drug, but not natural, reward is persistent.


Asunto(s)
Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Núcleo Accumbens/efectos de los fármacos , Recompensa , Interacción Social , Animales , Estimulantes del Sistema Nervioso Central/farmacología , AMP Cíclico/metabolismo , Masculino , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-Dawley
8.
Stem Cells ; 33(2): 574-88, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25331182

RESUMEN

Neural crest-derived stem cells (NCSCs) from the embryonic peripheral nervous system (PNS) can be reprogrammed in neurosphere (NS) culture to rNCSCs that produce central nervous system (CNS) progeny, including myelinating oligodendrocytes. Using global gene expression analysis we now demonstrate that rNCSCs completely lose their previous PNS characteristics and acquire the identity of neural stem cells derived from embryonic spinal cord. Reprogramming proceeds rapidly and results in a homogenous population of Olig2-, Sox3-, and Lex-positive CNS stem cells. Low-level expression of pluripotency inducing genes Oct4, Nanog, and Klf4 argues against a transient pluripotent state during reprogramming. The acquisition of CNS properties is prevented in the presence of BMP4 (BMP NCSCs) as shown by marker gene expression and the potential to produce PNS neurons and glia. In addition, genes characteristic for mesenchymal and perivascular progenitors are expressed, which suggests that BMP NCSCs are directed toward a pericyte progenitor/mesenchymal stem cell (MSC) fate. Adult NCSCs from mouse palate, an easily accessible source of adult NCSCs, display strikingly similar properties. They do not generate cells with CNS characteristics but lose the neural crest markers Sox10 and p75 and produce MSC-like cells. These findings show that embryonic NCSCs acquire a full CNS identity in NS culture. In contrast, MSC-like cells are generated from BMP NCSCs and pNCSCs, which reveals that postmigratory NCSCs are a source for MSC-like cells up to the adult stage.


Asunto(s)
Antígenos de Diferenciación/metabolismo , Embrión de Mamíferos/metabolismo , Cresta Neural/metabolismo , Células-Madre Neurales/metabolismo , Células Madre Pluripotentes/metabolismo , Médula Espinal/metabolismo , Animales , Diferenciación Celular/fisiología , Células Cultivadas , Embrión de Mamíferos/citología , Embrión de Mamíferos/embriología , Factor 4 Similar a Kruppel , Ratones , Cresta Neural/citología , Cresta Neural/embriología , Células-Madre Neurales/citología , Células Madre Pluripotentes/citología , Médula Espinal/citología , Médula Espinal/embriología
9.
J Neurosci ; 34(39): 13222-33, 2014 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-25253866

RESUMEN

After nerve injury, adult sensory neurons can regenerate peripheral axons and reconnect with their target tissue. Initiation of outgrowth, as well as elongation of neurites over long distances, depends on the signaling of receptors for neurotrophic growth factors. Here, we investigated the importance of gp130, the signaling subunit of neuropoietic cytokine receptors in peripheral nerve regeneration. After sciatic nerve crush, functional recovery in vivo was retarded in SNS-gp130(-/-) mice, which specifically lack gp130 in sensory neurons. Correspondingly, a significantly reduced number of free nerve endings was detected in glabrous skin from SNS-gp130(-/-) compared with control mice after nerve crush. Neurite outgrowth and STAT3 activation in vitro were severely reduced in cultures in gp130-deficient cultured neurons. Surprisingly, in neurons obtained from SNS-gp130(-/-) mice the increase in neurite length was reduced not only in response to neuropoietic cytokine ligands of gp130 but also to nerve growth factor (NGF), which does not bind to gp130-containing receptors. Neurite outgrowth in the absence of neurotrophic factors was partially rescued in gp130-deficient neurons by leptin, which activates STAT3 downstream of leptic receptor and independent of gp130. The neurite outgrowth response of gp130-deficient neurons to NGF was fully restored in the presence of leptin. Based on these findings, gp130 signaling via STAT3 activation is suggested not only to be an important regulator of peripheral nerve regeneration in vitro and in vivo, but as determining factor for the growth promoting action of NGF in adult sensory neurons.


Asunto(s)
Receptor gp130 de Citocinas/metabolismo , Regeneración Nerviosa , Neuritas/metabolismo , Factor de Transcripción STAT3/metabolismo , Nervio Ciático/fisiología , Células Receptoras Sensoriales/metabolismo , Animales , Procesos de Crecimiento Celular , Células Cultivadas , Receptor gp130 de Citocinas/genética , Leptina/farmacología , Ratones , Ratones Endogámicos C57BL , Factor de Crecimiento Nervioso/farmacología , Neuritas/efectos de los fármacos , Neuritas/fisiología , Fosforilación , Factor de Transcripción STAT3/genética , Nervio Ciático/citología , Nervio Ciático/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/fisiología
10.
Nucleic Acids Res ; 40(13): 6001-15, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22492625

RESUMEN

Protein-coding genes, guiding differentiation of ES cells into neural cells, have extensively been studied in the past. However, for the class of ncRNAs only the involvement of some specific microRNAs (miRNAs) has been described. Thus, to characterize the entire small non-coding RNA (ncRNA) transcriptome, involved in the differentiation of mouse ES cells into neural cells, we have generated three specialized ribonucleo-protein particle (RNP)-derived cDNA libraries, i.e. from pluripotent ES cells, neural progenitors and differentiated neural cells, respectively. By high-throughput sequencing and transcriptional profiling we identified several novel miRNAs to be involved in ES cell differentiation, as well as seven small nucleolar RNAs. In addition, expression of 7SL, 7SK and vault-2 RNAs was significantly up-regulated during ES cell differentiation. About half of ncRNA sequences from the three cDNA libraries mapped to intergenic or intragenic regions, designated as interRNAs and intraRNAs, respectively. Thereby, novel ncRNA candidates exhibited a predominant size of 18-30 nt, thus resembling miRNA species, but, with few exceptions, lacking canonical miRNA features. Additionally, these novel intraRNAs and interRNAs were not only found to be differentially expressed in stem-cell derivatives, but also in primary cultures of hippocampal neurons and astrocytes, strengthening their potential function in neural ES cell differentiation.


Asunto(s)
Diferenciación Celular/genética , Células Madre Embrionarias/metabolismo , Células-Madre Neurales/metabolismo , ARN no Traducido/metabolismo , Animales , Astrocitos/metabolismo , Línea Celular , Células Cultivadas , Células Madre Embrionarias/citología , Perfilación de la Expresión Génica , Biblioteca de Genes , Hipocampo/citología , Hipocampo/metabolismo , Ratones , MicroARNs/metabolismo , Células-Madre Neurales/citología , Neuronas/metabolismo , ARN no Traducido/química , Ribonucleoproteínas/metabolismo
11.
J Neurosci ; 31(34): 12059-67, 2011 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-21865449

RESUMEN

Although the p38 mitogen-activated protein kinases are active in many neuronal populations in the peripheral and central nervous systems, little is known about the physiological functions of p38 in postmitotic neurons. We report that p38 activity determines in vitro and in vivo the switch from noradrenergic to cholinergic neurotransmission that occurs in sympathetic neurons on exposure to the neuropoietic cytokines CNTF and LIF. This transdifferentiation serves as a model for the plastic mechanisms that enable mature neurons to change some of their central functions without passing through the cell cycle. We demonstrate that in postmitotic neurons, p38 and STAT pathways are concurrently activated by neuropoietic cytokine treatment for at least 12 h overlapping with changes in neurotransmitter marker gene expression. Inhibition of p38 blocks the upregulation of the nuclear matrix protein Satb2 and of cholinergic markers by CNTF without affecting STAT3 phosphorylation. Conversely, overexpression of p38α or ß in the absence of cytokines stimulates cholinergic marker expression. The neurotransmitter switch in vitro is impaired in neurons isolated from p38ß(-/-) mice. Consistent with these in vitro results, a substantial loss of cells expressing cholinergic properties is observed in vivo in the stellate ganglion of mature mice deficient in the p38ß isoform.


Asunto(s)
Acetilcolina/fisiología , Transdiferenciación Celular/genética , Neuronas Colinérgicas/enzimología , Proteína Quinasa 11 Activada por Mitógenos/genética , Proteína Quinasa 14 Activada por Mitógenos/genética , Ganglio Estrellado/enzimología , Animales , Animales Recién Nacidos , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Transdiferenciación Celular/efectos de los fármacos , Células Cultivadas , Neuronas Colinérgicas/citología , Neuronas Colinérgicas/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Quinasa 11 Activada por Mitógenos/deficiencia , Proteína Quinasa 14 Activada por Mitógenos/deficiencia , Neurotransmisores/genética , Neurotransmisores/fisiología , Ratas , Ratas Sprague-Dawley , Factores de Transcripción STAT/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Ganglio Estrellado/citología , Ganglio Estrellado/crecimiento & desarrollo
12.
Pharmacology ; 90(5-6): 264-73, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23018268

RESUMEN

Converging evidence from different independent laboratories suggests that acetylcholine may play an important role in drug reward and that modulation of the cholinergic system may be useful for the treatment of substance use disorders. In this commentary, we try to reconcile apparently discrepant animal behavioral, human behavioral and clinical data with a unifying hypothesis positing that the modulation of drug-versus natural stimuli-mediated reward by cholinergic interneurons in the nucleus accumbens (and the dorsal striatum) is restricted to distinct neuron ensembles that show considerable intra- and interindividual variation with respect to their spatial distribution. The precise targeting of these interindividually variable neuron ensembles would be a prerequisite for a successful pharmacotherapy based on the modulation of the cholinergic system. We also provide experimental data to support our unifying hypothesis.


Asunto(s)
Acetilcolina/fisiología , Ganglios Basales/fisiología , Recompensa , Trastornos Relacionados con Sustancias/fisiopatología , Animales , Cocaína , Condicionamiento Psicológico/fisiología , Proteína 1 de la Respuesta de Crecimiento Precoz/fisiología , Masculino , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley , Trastornos Relacionados con Sustancias/metabolismo
13.
Cells ; 11(6)2022 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-35326417

RESUMEN

The induction of lineage-specific gene programs are strongly influenced by alterations in local chromatin architecture. However, key players that impact this genome reorganization remain largely unknown. Here, we report that the removal of the special AT-rich binding protein 2 (SATB2), a nuclear protein known to bind matrix attachment regions, is a key event in initiating myogenic differentiation. The deletion of myoblast SATB2 in vitro initiates chromatin remodeling and accelerates differentiation, which is dependent on the caspase 7-mediated cleavage of SATB2. A genome-wide analysis indicates that SATB2 binding within chromatin loops and near anchor points influences both loop and sub-TAD domain formation. Consequently, the chromatin changes that occur with the removal of SATB2 lead to the derepression of differentiation-inducing factors while also limiting the expression of genes that inhibit this cell fate change. Taken together, this study demonstrates that the temporal control of the SATB2 protein is critical in shaping the chromatin environment and coordinating the myogenic differentiation program.


Asunto(s)
Proteínas de Unión a la Región de Fijación a la Matriz , Caspasas , Cromatina , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Mioblastos/metabolismo , Factores de Transcripción/metabolismo
14.
J Neurosci ; 30(48): 16356-64, 2010 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-21123581

RESUMEN

Sympathetic neurons can switch their neurotransmitter phenotype from noradrenergic to cholinergic on exposure to neuropoietic cytokines in vitro and in vivo. Here, we provide evidence that this transspecification is regulated by the chromatin architecture protein Satb2. Treatment with the neuropoietic cytokines ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor rapidly and strongly increases Satb2 transcript and protein levels in cultures of rat superior cervical ganglia neurons. Knockdown of endogenous Satb2 by short interfering RNA prevents the upregulation of choline acetyltransferase (Chat) and vesicular acetylcholine transporter (Vacht) by CNTF as well as the loss of norepinephrine transporter (Net). Conversely, overexpression of Satb2 in the noradrenergic sympathetic phenotype results in a marked increase of Chat and Vacht expression and reduced Net mRNA levels in the absence of neuropoietic cytokines. Chromatin immunoprecipitation analysis in primary sympathetic neurons reveals that Satb2 binds to matrix attachment regions (MARs) within the Chat locus. In vivo, in the rat stellate ganglion, Satb2 is expressed exclusively in sudomotor cholinergic neurons innervating the sweat glands and only after establishment of contact between neurons and target. These findings demonstrate a function of the MAR-binding protein Satb2 in growth factor-dependent neurotransmitter plasticity in postmitotic neurons.


Asunto(s)
Proteínas de Unión a la Región de Fijación a la Matriz/fisiología , Neurotransmisores/fisiología , Ganglio Cervical Superior/fisiología , Factores de Transcripción/fisiología , Fibras Adrenérgicas/fisiología , Animales , Animales Recién Nacidos , Células Cultivadas , Técnicas de Silenciamiento del Gen , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Mitosis/genética , Mitosis/fisiología , Plasticidad Neuronal/genética , Plasticidad Neuronal/fisiología , Neurotransmisores/genética , Proteínas Asociadas a Matriz Nuclear/genética , Proteínas Asociadas a Matriz Nuclear/fisiología , Ratas , Factores de Transcripción/genética
15.
Addict Biol ; 16(2): 273-84, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21309948

RESUMEN

Little is known how social interaction, if offered as an alternative to drug consumption, affects neural circuits involved in drug reinforcement and substance dependence. Conditioned place preference (CPP) for cocaine (15 mg/kg i.p.) or social interaction (15 minutes) as an alternative stimulus was investigated in male Sprague-Dawley rats. Four social interaction episodes with a male adult conspecific completely reversed cocaine CPP and were even able to prevent reacquisition of cocaine CPP. Social interaction also reversed cocaine CPP-induced expression of the immediate-early gene zif268 in the nucleus accumbens shell, the central and basolateral amygdala and the ventral tegmental area. These findings suggest that social interaction, if offered in a context that is clearly distinct from the previously drug-associated ones, may profoundly decrease the incentive salience of drug-associated contextual stimuli. The novel experimental design facilitates the neurobiological investigation of this phenomenon which may be beneficial for human drug users in treatment.


Asunto(s)
Corteza Cerebral/fisiopatología , Trastornos Relacionados con Cocaína/genética , Condicionamiento Psicológico/fisiología , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Sistema Límbico/fisiopatología , Mesencéfalo/fisiopatología , Conducta Social , Animales , Mapeo Encefálico , Conducta de Elección , Trastornos Relacionados con Cocaína/fisiopatología , Trastornos Relacionados con Cocaína/psicología , Extinción Psicológica/fisiología , Masculino , Motivación/fisiología , Red Nerviosa/fisiopatología , Ratas , Ratas Sprague-Dawley , Síndrome de Abstinencia a Sustancias/genética , Síndrome de Abstinencia a Sustancias/fisiopatología , Síndrome de Abstinencia a Sustancias/psicología
16.
J Neurosci Res ; 87(7): 1679-85, 2009 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-19115416

RESUMEN

Progressive degeneration of striatal projection neurons is thought to account for the loss of L-Dopa response observed in the majority of patients with the parkinsonian variant of multiple system atrophy (MSA-P). Here we have investigated the effects of E14 embryonic striatal allografts on dopaminergic responsiveness in the unilateral double-lesion rat model of MSA-P by using tests of complex motor behavior. Both sham and graft animals showed an increase in apomorphine-induced rotations as well as an improvement in cylinder test performance following surgical intervention. In contrast, L-Dopa responsiveness of stepping behavior was improved only in grafted animals. The restoration of apomorphine-induced rotation correlated with the P-zone volume of grafts. Our findings indicate that transplantation of embryonic striatal grafts might, at least to some extent, restore responsiveness to L-Dopa in tasks of complex motor behavior. Therefore, striatal transplantation should be further defined preclinically as a possible therapeutic option for patients with MSA-P and a failing L-Dopa response.


Asunto(s)
Cuerpo Estriado/trasplante , Dopaminérgicos/uso terapéutico , Levodopa/uso terapéutico , Atrofia de Múltiples Sistemas/terapia , Análisis de Varianza , Animales , Apomorfina/farmacología , Encéfalo/patología , Cuerpo Estriado/embriología , Modelos Animales de Enfermedad , Masculino , Actividad Motora/efectos de los fármacos , Atrofia de Múltiples Sistemas/tratamiento farmacológico , Atrofia de Múltiples Sistemas/fisiopatología , Distribución Aleatoria , Ratas , Ratas Wistar , Trasplante Homólogo
17.
Neuron ; 33(2): 156-8, 2002 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-11804563

RESUMEN

In this issue of Neuron, show that in rodent SCG neurons NGF activates Ret, the signaling component of the multisubunit GDNF receptor, in vitro and in vivo by a mechanism, which is independent of GFL ligands and GFRalpha coreceptors. NGF-dependent Ret phosphorylation regulates soma size and metabolism but not survival of maturing postnatal sympathetic neurons.


Asunto(s)
Proteínas de Drosophila , Factor de Crecimiento Nervioso/fisiología , Proteínas Tirosina Quinasas/fisiología , Proteínas Proto-Oncogénicas/fisiología , Proteínas Tirosina Quinasas Receptoras/fisiología , Transducción de Señal/fisiología , Animales , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial , Proteínas Proto-Oncogénicas c-ret , Ratas
18.
J Virol ; 81(24): 13622-30, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17928338

RESUMEN

Rabies virus glycoprotein (RVG) is known to be the only factor that mediates rabies infection. The neurotrophin receptor (p75(NTR)), through its cysteine-rich domain 1, is a specific receptor for RVG and neutralizes virus infectivity, but its role in virus infection has remained obscure. We used adult mouse dorsal root ganglion (DRG) neurons as a model to study the role of p75(NTR) in RV infection of primary neurons. We show that RV infects around 20% of DRG neurons, of which more than 80% are p75(NTR) positive, have large diameters, and are capsaicin insensitive. Surprisingly, RV binding and infection are absent in about half of the p75(NTR)-expressing DRG neurons which have small diameters and are often capsaicin sensitive. This indicates that p75(NTR) is not sufficient to mediate RV interaction in sensory neurons. The rate and specificity of neural infection are unchanged in RV-infected p75(NTRExonIV-/-) mice that lack all extracellular receptor domains and in wild-type mice infected with two independent RV mutants that lack p75(NTR) binding. Accordingly, the mortality rate is unchanged in the absence of RV-p75(NTR) interaction. We conclude that although p75(NTR) is a receptor for soluble RVG in transfected cells of heterologous expression systems, an RVG-p75(NTR) interaction is not necessary for RV infection of primary neurons. This means that other receptors are required to mediate RV infection in vivo and in vitro.


Asunto(s)
Virus de la Rabia/patogenicidad , Rabia/virología , Receptores de Factor de Crecimiento Nervioso/metabolismo , Receptores Virales/metabolismo , Animales , Antígenos Virales/metabolismo , Células COS , Células Cultivadas , Chlorocebus aethiops , Femenino , Ganglios Espinales/citología , Ganglios Espinales/virología , Glicoproteínas/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neuronas/citología , Neuronas/virología , Receptores de Factor de Crecimiento Nervioso/deficiencia , Receptores de Factor de Crecimiento Nervioso/genética , Proteínas del Envoltorio Viral/metabolismo
19.
Nat Neurosci ; 5(11): 1131-6, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12404007

RESUMEN

Neurotrophins have long been known to promote the survival and differentiation of vertebrate neurons. However, these growth factors can also induce cell death through the p75 neurotrophin receptor (p75(NTR)), a member of the tumor necrosis factor receptor superfamily. Consistent with a function in controlling the survival and process formation of neurons, p75(NTR) is mainly expressed during early neuronal development. In the adult, p75(NTR) is re-expressed in various pathological conditions, including epilepsy, axotomy and neurodegeneration. Potentially toxic peptides, including the amyloid beta- (Abeta-) peptide that accumulates in Alzheimer's disease, are ligands for p75(NTR). Recent work also implicates p75(NTR) in the regulation of both synaptic transmission and axonal elongation. It associates with the Nogo receptor, a binding protein for axonal growth inhibitors, and appears to be the transducing subunit of this receptor complex.


Asunto(s)
Enfermedades del Sistema Nervioso/fisiopatología , Receptores de Factor de Crecimiento Nervioso/fisiología , Animales , Axones/fisiología , Muerte Celular/fisiología , Humanos , Receptor de Factor de Crecimiento Nervioso , Transmisión Sináptica/fisiología
20.
Front Behav Neurosci ; 12: 224, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30356831

RESUMEN

SATB2 is a DNA binding protein that specifically binds the nuclear matrix attachment region and functions as a regulator of the transcription of large chromatin domains. Unlike its well addressed role during brain development, the role of SATB2 in adult brain is under-investigated. It has been shown that deletion of SATB2 from the forebrain of adult mice significantly impaired long-term memory for contextual fear and object recognition memory. The aim of the present study was to investigate the effects of appetitive stimuli such as cocaine and social interaction (SI) on SATB2 expression in the adult rat brain. For that, we performed conditioned place preference (CPP) to cocaine (15 mg/kg) and to SI, then assessed SATB2 expression in the brain 1 h (24 h after the last conditioning) and 24 h (48 h after the last conditioning) after the CPP test. We found that SATB2 expression in the paraventricular thalamus of rats was increased 1 h after the cocaine CPP test. This increase was selective for the cocaine-paired environment since the SI-paired environment did not increase SATB2 expression in the paraventricular thalamus. Also, the cocaine paired environment-induced increase of SATB2 levels in the paraventricular thalamus was due to cocaine conditioning as the unpaired cocaine group did not show an increase of SATB2 in the paraventricular thalamus. These results suggest that SATB2 in the paraventricular thalamus appears to be involved in the association between cocaine effects and environmental context. Further studies are needed to address the functional role of SATB2 in cocaine conditioning.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA