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1.
Proc Natl Acad Sci U S A ; 120(44): e2310344120, 2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37871205

RESUMO

Mutations in MECP2 give rise to Rett syndrome (RTT), an X-linked neurodevelopmental disorder that results in broad cognitive impairments in females. While the exact etiology of RTT symptoms remains unknown, one possible explanation for its clinical presentation is that loss of MECP2 causes miswiring of neural circuits due to defects in the brain's capacity to respond to changes in neuronal activity and sensory experience. Here, we show that MeCP2 is phosphorylated at four residues in the mouse brain (S86, S274, T308, and S421) in response to neuronal activity, and we generate a quadruple knock-in (QKI) mouse line in which all four activity-dependent sites are mutated to alanines to prevent phosphorylation. QKI mice do not display overt RTT phenotypes or detectable gene expression changes in two brain regions. However, electrophysiological recordings from the retinogeniculate synapse of QKI mice reveal that while synapse elimination is initially normal at P14, it is significantly compromised at P20. Notably, this phenotype is distinct from the synapse refinement defect previously reported for Mecp2 null mice, where synapses initially refine but then regress after the third postnatal week. We thus propose a model in which activity-induced phosphorylation of MeCP2 is critical for the proper timing of retinogeniculate synapse maturation specifically during the early postnatal period.


Assuntos
Proteína 2 de Ligação a Metil-CpG , Síndrome de Rett , Feminino , Camundongos , Animais , Fosforilação , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Encéfalo/metabolismo , Sinapses/metabolismo , Neurônios/metabolismo , Camundongos Knockout , Modelos Animais de Doenças
2.
Nature ; 539(7628): 242-247, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27830782

RESUMO

Sensory stimuli drive the maturation and function of the mammalian nervous system in part through the activation of gene expression networks that regulate synapse development and plasticity. These networks have primarily been studied in mice, and it is not known whether there are species- or clade-specific activity-regulated genes that control features of brain development and function. Here we use transcriptional profiling of human fetal brain cultures to identify an activity-dependent secreted factor, Osteocrin (OSTN), that is induced by membrane depolarization of human but not mouse neurons. We find that OSTN has been repurposed in primates through the evolutionary acquisition of DNA regulatory elements that bind the activity-regulated transcription factor MEF2. In addition, we demonstrate that OSTN is expressed in primate neocortex and restricts activity-dependent dendritic growth in human neurons. These findings suggest that, in response to sensory input, OSTN regulates features of neuronal structure and function that are unique to primates.


Assuntos
Evolução Molecular , Proteínas Musculares/metabolismo , Neocórtex/metabolismo , Neurônios/metabolismo , Fatores de Transcrição/metabolismo , Transcriptoma , Animais , Sequência de Bases , Osso e Ossos/metabolismo , Dendritos/metabolismo , Elementos Facilitadores Genéticos/genética , Feminino , Humanos , Fatores de Transcrição MEF2/metabolismo , Macaca mulatta , Masculino , Camundongos , Dados de Sequência Molecular , Proteínas Musculares/genética , Músculos/metabolismo , Neocórtex/citologia , Neurônios/citologia , Especificidade de Órgãos , Especificidade da Espécie , Fatores de Transcrição/genética
3.
Appl Geochem ; 119: 1-104632, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33746355

RESUMO

Urbanization contributes to the formation of novel elemental combinations and signatures in terrestrial and aquatic watersheds, also known as 'chemical cocktails.' The composition of chemical cocktails evolves across space and time due to: (1) elevated concentrations from anthropogenic sources, (2) accelerated weathering and corrosion of the built environment, (3) increased drainage density and intensification of urban water conveyance systems, and (4) enhanced rates of geochemical transformations due to changes in temperature, ionic strength, pH, and redox potentials. Characterizing chemical cocktails and underlying geochemical processes is necessary for: (1) tracking pollution sources using complex chemical mixtures instead of individual elements or compounds; (2) developing new strategies for co-managing groups of contaminants; (3) identifying proxies for predicting transport of chemical mixtures using continuous sensor data; and (4) determining whether interactive effects of chemical cocktails produce ecosystem-scale impacts greater than the sum of individual chemical stressors. First, we discuss some unique urban geochemical processes which form chemical cocktails, such as urban soil formation, human-accelerated weathering, urban acidification-alkalinization, and freshwater salinization syndrome. Second, we review and synthesize global patterns in concentrations of major ions, carbon and nutrients, and trace elements in urban streams across different world regions and make comparisons with reference conditions. In addition to our global analysis, we highlight examples from some watersheds in the Baltimore-Washington DC region, which show increased transport of major ions, trace metals, and nutrients across streams draining a well-defined land-use gradient. Urbanization increased the concentrations of multiple major and trace elements in streams draining human-dominated watersheds compared to reference conditions. Chemical cocktails of major and trace elements were formed over diurnal cycles coinciding with changes in streamflow, dissolved oxygen, pH, and other variables measured by high-frequency sensors. Some chemical cocktails of major and trace elements were also significantly related to specific conductance (p<0.05), which can be measured by sensors. Concentrations of major and trace elements increased, peaked, or decreased longitudinally along streams as watershed urbanization increased, which is consistent with distinct shifts in chemical mixtures upstream and downstream of other major cities in the world. Our global analysis of urban streams shows that concentrations of multiple elements along the Periodic Table significantly increase when compared with reference conditions. Furthermore, similar biogeochemical patterns and processes can be grouped among distinct mixtures of elements of major ions, dissolved organic matter, nutrients, and trace elements as chemical cocktails. Chemical cocktails form in urban waters over diurnal cycles, decades, and throughout drainage basins. We conclude our global review and synthesis by proposing strategies for monitoring and managing chemical cocktails using source control, ecosystem restoration, and green infrastructure. We discuss future research directions applying the watershed chemical cocktail approach to diagnose and manage environmental problems. Ultimately, a chemical cocktail approach targeting sources, transport, and transformations of different and distinct elemental combinations is necessary to more holistically monitor and manage the emerging impacts of chemical mixtures in the world's fresh waters.

4.
J Nanosci Nanotechnol ; 14(7): 4918-29, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24757963

RESUMO

Carbon nanotubes (CNTs) and sepiolite (SEP) were modified in order to improve their compatibility with the polypropylene (PP) matrix. Carboxylic groups were introduced into the CNTs through an oxidative treatment and aliphatic chains were incorporated on SEP by ion exchange of a cationic surfactant. Maleic anhydride grafted polypropylene (PPgMA) was mixed with neat PP to introduce polar groups into the polymer matrix. Composites including modified and non-modified fillers were prepared by melt extrusion. Dispersion and interaction of the CNTs with the PP and PPgMA matrices were evaluated by Raman spectroscopy while a focused ion beam/scanning electron microscopy (FIB/SEM) was used for SEP containing composites. Scratch resistance, microhardness, dynamic friction and wear were determined. Raman spectroscopy shows that the introduction of polar groups into PP matrices has a positive effect on the dispersion of modified CNTs. FIB/SEM results show that the modification of SEP improves its dispersion in the polypropylene matrix; filler clusters found in the PPgMA matrix are much times smaller than those in the neat PP. Despite of SEP agglomerates in the composites, a good interaction between both phases is seen; SEP particles are fully coated and embedded inside the PP matrix. The 'lack of cooperation' between unmodified PP and its fillers results in nanocomposites with larger residual depths; by contrast, PPgMA does 'cooperate' with its fillers so that the nanocomposites in scratch resistance testing have smaller residual depths R(h) than the neat PPgMA. Addition of the fillers to PPgMA also increases the hardness. As for wear rates, some our fillers provide higher and some lower wear rates than PP.

5.
bioRxiv ; 2023 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-37461668

RESUMO

Mutations in MECP2 give rise to Rett syndrome (RTT), an X-linked neurodevelopmental disorder that results in broad cognitive impairments in females. While the exact etiology of RTT symptoms remains unknown, one possible explanation for its clinical presentation is that loss of MeCP2 causes miswiring of neural circuits due to defects in the brain's capacity to respond to changes in neuronal activity and sensory experience. Here we show that MeCP2 is phosphorylated at four residues in the brain (S86, S274, T308, and S421) in response to neuronal activity, and we generate a quadruple knock-in (QKI) mouse line in which all four activity-dependent sites are mutated to alanines to prevent phosphorylation. QKI mice do not display overt RTT phenotypes or detectable gene expression changes in two brain regions. However, electrophysiological recordings from the retinogeniculate synapse of QKI mice reveal that while synapse elimination is initially normal at P14, it is significantly compromised at P20. Notably, this phenotype is distinct from that previously reported for Mecp2 null mice, where synapses initially refine but then regress after the third postnatal week. We thus propose a model in which activity-induced phosphorylation of MeCP2 is critical for the proper timing of retinogeniculate synapse maturation specifically during the early postnatal period. SIGNIFICANCE STATEMENT: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that predominantly affects girls. RTT is caused by loss of function mutations in a single gene MeCP2. Girls with RTT develop normally during their first year of life, but then experience neurological abnormalities including breathing and movement difficulties, loss of speech, and seizures. This study investigates the function of the MeCP2 protein in the brain, and how MeCP2 activity is modulated by sensory experience in early life. Evidence is presented that sensory experience affects MeCP2 function, and that this is required for synaptic pruning in the brain. These findings provide insight into MeCP2 function, and clues as to what goes awry in the brain when the function of MeCP2 is disrupted.

6.
Nat Neurosci ; 24(3): 437-448, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33542524

RESUMO

Neuronal activity-dependent gene expression is essential for brain development. Although transcriptional and epigenetic effects of neuronal activity have been explored in mice, such an investigation is lacking in humans. Because alterations in GABAergic neuronal circuits are implicated in neurological disorders, we conducted a comprehensive activity-dependent transcriptional and epigenetic profiling of human induced pluripotent stem cell-derived GABAergic neurons similar to those of the early developing striatum. We identified genes whose expression is inducible after membrane depolarization, some of which have specifically evolved in primates and/or are associated with neurological diseases, including schizophrenia and autism spectrum disorder (ASD). We define the genome-wide profile of human neuronal activity-dependent enhancers, promoters and the transcription factors CREB and CRTC1. We found significant heritability enrichment for ASD in the inducible promoters. Our results suggest that sequence variation within activity-inducible promoters of developing human forebrain GABAergic neurons contributes to ASD risk.


Assuntos
Encéfalo/metabolismo , Epigênese Genética , Neurônios GABAérgicos/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Regiões Promotoras Genéticas
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