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1.
J Neuroinflammation ; 19(1): 250, 2022 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-36203187

RESUMEN

BACKGROUND: Immunosurveillance of the central nervous system (CNS) is vital to resolve infection and injury. However, immune activation within the CNS in the setting of chronic viral infections, such as HIV-1, is strongly linked to progressive neurodegeneration and cognitive decline. Establishment of HIV-1 in the CNS early following infection underscores the need to delineate features of acute CNS immune activation, as these early inflammatory events may mediate neurodegenerative processes. Here, we focused on elucidating molecular programs of neuroinflammation in brain regions based on vulnerability to neuroAIDS and/or neurocognitive decline. To this end, we assessed transcriptional profiles within the subcortical white matter of the pre-frontal cortex (PFCw), as well as synapse dense regions from hippocampus, superior temporal cortex, and caudate nucleus, in rhesus macaques following infection with Simian/Human Immunodeficiency Virus (SHIV.C.CH505). METHODS: We performed RNA extraction and sequenced RNA isolated from 3 mm brain punches. Viral RNA was quantified in the brain and cerebrospinal fluid by RT-qPCR assays targeting SIV Gag. Neuroinflammation was assessed by flow cytometry and multiplex ELISA assays. RESULTS: RNA sequencing and flow cytometry data demonstrated immune surveillance of the rhesus CNS by innate and adaptive immune cells during homeostasis. Following SHIV infection, viral entry and integration within multiple brain regions demonstrated vulnerabilities of key cognitive and motor function brain regions to HIV-1 during the acute phase of infection. SHIV-induced transcriptional alterations were concentrated to the PFCw and STS with upregulation of gene expression pathways controlling innate and T-cell inflammatory responses. Within the PFCw, gene modules regulating microglial activation and T cell differentiation were induced at 28 days post-SHIV infection, with evidence for stimulation of immune effector programs characteristic of neuroinflammation. Furthermore, enrichment of pathways regulating mitochondrial respiratory capacity, synapse assembly, and oxidative and endoplasmic reticulum stress were observed. These acute neuroinflammatory features were substantiated by increased influx of activated T cells into the CNS. CONCLUSIONS: Our data show pervasive immune surveillance of the rhesus CNS at homeostasis and reveal perturbations of important immune, neuronal, and synaptic pathways within key anatomic regions controlling cognition and motor function during acute HIV infection. These findings provide a valuable framework to understand early molecular features of HIV associated neurodegeneration.


Asunto(s)
Infecciones por VIH , VIH-1 , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Sustancia Blanca , Animales , Lóbulo Frontal , VIH-1/genética , Humanos , Macaca mulatta/genética , ARN Viral , Carga Viral
2.
Cell Rep ; 39(10): 110853, 2022 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-35675768

RESUMEN

Fragile X syndrome (FXS) is a leading cause of inherited intellectual disability and autism. Whereas dysregulated RNA translation in Fmr1 knockout (KO) mice, a model of FXS, is well studied, little is known about aberrant transcription. Using single-molecule mRNA detection, we show that mRNA encoding the AMPAR subunit GluA2 (but not GluA1) is elevated in dendrites and at transcription sites of hippocampal neurons of Fmr1 KO mice, indicating elevated GluA2 transcription. We identify CPEB3, a protein implicated in memory consolidation, as an upstream effector critical to GluA2 mRNA expression in FXS. Increased GluA2 mRNA is translated into an increase in GluA2 subunits, a switch in synaptic AMPAR phenotype from GluA2-lacking, Ca2+-permeable to GluA2-containing, Ca2+-impermeable, reduced inhibitory synaptic transmission, and loss of NMDAR-independent LTP at glutamatergic synapses onto CA1 inhibitory interneurons. These factors could contribute to an excitatory/inhibitory imbalance-a common theme in FXS and other autism spectrum disorders.


Asunto(s)
Síndrome del Cromosoma X Frágil , Proteínas de Unión al ARN , Receptores AMPA , Animales , Modelos Animales de Enfermedad , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/genética , Interneuronas/metabolismo , Ratones , Ratones Noqueados , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo
3.
Genome Med ; 13(1): 69, 2021 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-33910599

RESUMEN

BACKGROUND: Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the NaV1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in SCN1A are associated with epilepsy, including Dravet syndrome (DS). The majority of DS patients harbor coding mutations causing SCN1A haploinsufficiency; however, putative causal non-coding promoter mutations have been identified. METHODS: To determine the functional role of one of these potentially redundant Scn1a promoters, we focused on the non-coding Scn1a 1b regulatory region, previously described as a non-canonical alternative transcriptional start site. We generated a transgenic mouse line with deletion of the extended evolutionarily conserved 1b non-coding interval and characterized changes in gene and protein expression, and assessed seizure activity and alterations in behavior. RESULTS: Mice harboring a deletion of the 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and NaV1.1 expression throughout the brain. This was accompanied by electroencephalographic and thermal-evoked seizures, and behavioral deficits. CONCLUSIONS: This work contributes to functional dissection of the regulatory wiring of a major epilepsy risk gene, SCN1A. We identified the 1b region as a critical disease-relevant regulatory element and provide evidence that non-canonical and seemingly redundant promoters can have essential function.


Asunto(s)
Epilepsia/genética , Regulación de la Expresión Génica , Canal de Sodio Activado por Voltaje NAV1.1/genética , Eliminación de Secuencia/genética , Animales , Atención , Secuencia de Bases , Encéfalo/metabolismo , Encéfalo/patología , Cromatina/metabolismo , Secuencia Conservada/genética , Modelos Animales de Enfermedad , Electroencefalografía , Epilepsia/diagnóstico por imagen , Evolución Molecular , Femenino , Células HEK293 , Heterocigoto , Homocigoto , Humanos , Masculino , Aprendizaje por Laberinto , Trastornos de la Memoria/genética , Ratones Endogámicos C57BL , Neuronas/metabolismo , Prueba de Campo Abierto , Fenotipo , Unión Proteica , Secuencias Reguladoras de Ácidos Nucleicos/genética , Análisis de Supervivencia , Temperatura , Transactivadores/metabolismo
4.
Nat Neurosci ; 20(8): 1062-1073, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28671691

RESUMEN

The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8+/del5 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8+/del5 mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8+/del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes and neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8+/del5 mice. This integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development.


Asunto(s)
Proteínas de Unión al ADN/genética , Regulación del Desarrollo de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Haploinsuficiencia/genética , Animales , Encéfalo/metabolismo , Proteínas de Ciclo Celular/genética , Cromatina/metabolismo , Ratones Transgénicos , Mutación/genética , Fenotipo , Factores de Transcripción/genética
5.
Biochem Biophys Res Commun ; 377(2): 434-440, 2008 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-18930031

RESUMEN

Embryonic stem cells (ESCs) and embryonal carcinoma cells (ECCs) possess the remarkable property of self-renewal and differentiation potency. They are model preparations for investigating the underlying mechanisms of "stemness". microRNAs are recently discovered small noncoding RNAs with a broad spectrum of functions, especially in control of development. Here, we show that miR-302b indirectly regulates expression of the pluripotent stem cell marker Oct4, and it directly regulates expression of Cyclin D2 protein, a developmental regulator during gastrulation. Using loss-of function and gain-of function approaches, we demonstrate that functional miR-302b is necessary to maintain stem cell self-renewal and inhibit neuronal differentiation of human ECCs. During retinoic acid-induced neuronal differentiation, Cyclin D2 protein but not mRNA expression is strongly increased, concurrent with the down-regulation of miR-302b and Oct4. Our results suggest that miR-302b plays an important role in maintaining the pluripotency of ECCs and probably ESCs, by post-transcriptional regulation of Cyclin D2 expression.


Asunto(s)
Ciclinas/biosíntesis , Células Madre de Carcinoma Embrionario/metabolismo , MicroARNs/fisiología , Células Madre Pluripotentes/metabolismo , Biosíntesis de Proteínas , Diferenciación Celular , Línea Celular Tumoral , Ciclina D2 , Ciclinas/genética , Células Madre de Carcinoma Embrionario/citología , Regulación de la Expresión Génica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Células Madre Pluripotentes/citología , Biosíntesis de Proteínas/genética , ARN Mensajero/biosíntesis , Activación Transcripcional
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