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1.
Nat Commun ; 15(1): 4632, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951500

RESUMO

ANKRD11 (Ankyrin Repeat Domain 11) is a chromatin regulator and a causative gene for KBG syndrome, a rare developmental disorder characterized by multiple organ abnormalities, including cardiac defects. However, the role of ANKRD11 in heart development is unknown. The neural crest plays a leading role in embryonic heart development, and its dysfunction is implicated in congenital heart defects. We demonstrate that conditional knockout of Ankrd11 in the murine embryonic neural crest results in persistent truncus arteriosus, ventricular dilation, and impaired ventricular contractility. We further show these defects occur due to aberrant cardiac neural crest cell organization leading to outflow tract septation failure. Lastly, knockout of Ankrd11 in the neural crest leads to impaired expression of various transcription factors, chromatin remodelers and signaling pathways, including mTOR, BMP and TGF-ß in the cardiac neural crest cells. In this work, we identify Ankrd11 as a regulator of neural crest-mediated heart development and function.


Assuntos
Cardiopatias Congênitas , Coração , Camundongos Knockout , Crista Neural , Proteínas Repressoras , Animais , Crista Neural/metabolismo , Crista Neural/embriologia , Camundongos , Coração/embriologia , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Regulação da Expressão Gênica no Desenvolvimento , Cromatina/metabolismo , Transdução de Sinais , Miocárdio/metabolismo , Feminino
2.
Stem Cell Rev Rep ; 19(4): 983-1000, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36617597

RESUMO

The mammalian adult brain contains two neural stem and precursor (NPC) niches: the subventricular zone [SVZ] lining the lateral ventricles and the subgranular zone [SGZ] in the hippocampus. From these, SVZ NPCs represent the largest NPC pool. While SGZ NPCs typically only produce neurons and astrocytes, SVZ NPCs produce neurons, astrocytes and oligodendrocytes throughout life. Of particular importance is the generation and replacement of oligodendrocytes, the only myelinating cells of the central nervous system (CNS). SVZ NPCs contribute to myelination by regenerating the parenchymal oligodendrocyte precursor cell (OPC) pool and by differentiating into oligodendrocytes in the developing and demyelinated brain. The neurosphere assay has been widely adopted by the scientific community to facilitate the study of NPCs in vitro. Here, we present a streamlined protocol for culturing postnatal and adult SVZ NPCs and OPCs from primary neurosphere cells. We characterize the purity and differentiation potential as well as provide RNA-sequencing profiles of postnatal SVZ NPCs, postnatal SVZ OPCs and adult SVZ NPCs. We show that primary neurospheres cells generated from postnatal and adult SVZ differentiate into neurons, astrocytes and oligodendrocytes concurrently and at comparable levels. SVZ OPCs are generated by subjecting primary neurosphere cells to OPC growth factors fibroblast growth factor (FGF) and platelet-derived growth factor-AA (PDGF-AA). We further show SVZ OPCs can differentiate into oligodendrocytes in the absence and presence of thyroid hormone T3. Transcriptomic analysis confirmed the identities of each cell population and revealed novel immune and signalling pathways expressed in an age and cell type specific manner.


Assuntos
Ventrículos Laterais , Transcriptoma , Camundongos , Animais , Transcriptoma/genética , Encéfalo , Neurônios , Diferenciação Celular/genética , Fatores de Crescimento de Fibroblastos , Mamíferos
3.
Stem Cell Reports ; 18(2): 519-533, 2023 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-36608690

RESUMO

Demyelinating disorders of the central nervous system (CNS) occur when myelin and oligodendrocytes are damaged or lost. Remyelination and regeneration of oligodendrocytes can be achieved from endogenous oligodendrocyte precursor cells (OPCs) that reside in the adult CNS tissue. Using a cuprizone mouse model of demyelination, we show that infusion of fractalkine (CX3CL1) into the demyelinated murine brain increases de novo oligodendrocyte formation and enhances remyelination in the corpus callosum and cortical gray matter. This is achieved by increased OPC proliferation in the cortical gray matter as well as OPC differentiation and attenuation of microglia/macrophage activation both in corpus callosum and cortical gray matter. Finally, we show that activated OPCs and microglia/macrophages express fractalkine receptor CX3CR1 in vivo, and that in OPC-microglia co-cultures fractalkine increases in vitro oligodendrocyte differentiation by modulating both OPC and microglia biology. Our results demonstrate a novel pro-regenerative role of fractalkine in a demyelinating mouse model.


Assuntos
Doenças Desmielinizantes , Remielinização , Camundongos , Animais , Quimiocina CX3CL1 , Oligodendroglia/fisiologia , Bainha de Mielina , Modelos Animais de Doenças , Diferenciação Celular/fisiologia , Camundongos Endogâmicos C57BL
4.
Psychol Rev ; 129(6): 1249-1280, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-34968136

RESUMO

Whereas both human and animal lesion and human neuroimaging studies have implicated the hippocampus in memory for associations, some studies find preserved associative memory following hippocampal damage. Starting with a classic summed similarity model of item recognition, we can account for associative recognition without assuming a specific hippocampally-mediated associative process. We add one key assumption: that one item can influence activation of another item's features. Feature-strength patterns, evaluated for each probe item individually, are then diagnostic of whether an item was paired with one item versus another. We suggest that feature-level inference, without explicit storage of associations, may play a critical role in associative recognition tasks. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Assuntos
Hipocampo , Reconhecimento Psicológico , Animais , Humanos , Reconhecimento Psicológico/fisiologia , Hipocampo/fisiologia , Aprendizagem por Associação/fisiologia
5.
Stem Cell Reports ; 16(8): 1968-1984, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34270934

RESUMO

Neural and oligodendrocyte precursor cells (NPCs and OPCs) in the subventricular zone (SVZ) of the brain contribute to oligodendrogenesis throughout life, in part due to direct regulation by chemokines. The role of the chemokine fractalkine is well established in microglia; however, the effect of fractalkine on SVZ precursor cells is unknown. We show that murine SVZ NPCs and OPCs express the fractalkine receptor (CX3CR1) and bind fractalkine. Exogenous fractalkine directly enhances OPC and oligodendrocyte genesis from SVZ NPCs in vitro. Infusion of fractalkine into the lateral ventricle of adult NPC lineage-tracing mice leads to increased newborn OPC and oligodendrocyte formation in vivo. We also show that OPCs secrete fractalkine and that inhibition of endogenous fractalkine signaling reduces oligodendrocyte formation in vitro. Finally, we show that fractalkine signaling regulates oligodendrogenesis in cerebellar slices ex vivo. In summary, we demonstrate a novel role for fractalkine signaling in regulating oligodendrocyte genesis from postnatal CNS precursor cells.


Assuntos
Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Ventrículos Laterais/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Transdução de Sinais , Animais , Receptor 1 de Quimiocina CX3C/genética , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células Cultivadas , Quimiocina CX3CL1/farmacologia , Expressão Gênica/efeitos dos fármacos , Ventrículos Laterais/citologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Células Precursoras de Oligodendrócitos/citologia , Fator de Transcrição 2 de Oligodendrócitos/genética , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Oligodendroglia/citologia , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo
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