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1.
EMBO Rep ; 22(2): e51127, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33410253

RESUMO

Centrosomes, composed of two centrioles and pericentriolar material, organize mitotic spindles during cell division and template cilia during interphase. The first few divisions during mouse development occur without centrioles, which form around embryonic day (E) 3. However, disruption of centriole biogenesis in Sas-4 null mice leads to embryonic arrest around E9. Centriole loss in Sas-4-/- embryos causes prolonged mitosis and p53-dependent cell death. Studies in vitro discovered a similar USP28-, 53BP1-, and p53-dependent mitotic surveillance pathway that leads to cell cycle arrest. In this study, we show that an analogous pathway is conserved in vivo where 53BP1 and USP28 are upstream of p53 in Sas-4-/- embryos. The data indicate that the pathway is established around E7 of development, four days after the centrioles appear. Our data suggest that the newly formed centrioles gradually mature to participate in mitosis and cilia formation around the beginning of gastrulation, coinciding with the activation of mitotic surveillance pathway upon centriole loss.


Assuntos
Centríolos , Centrossomo , Animais , Interfase , Camundongos , Mitose/genética , Fuso Acromático
2.
Alzheimers Dement ; 19(11): 5086-5094, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37104247

RESUMO

INTRODUCTION: The influence of apolipoprotein E (APOE) genotype on mild cognitive impairment (MCI) and Alzheimer's disease (AD) is well studied in the non-Hispanic white (NHW) population but not in the Hispanic population. Additionally, health risk factors such as hypertension, stroke, and depression may also differ between the two populations. METHODS: We combined three data sets (National Alzheimer's Coordinating Center [NACC], Alzheimer's Disease Neuroimaging Initiative [ADNI], Health and Aging Brain Study: Health Disparities [HABS-HD]) and compared risk factors for MCI and AD between Hispanic and NHW participants, with a total of 24,268 participants (11.1% Hispanic). RESULTS: APOEε4 was associated with fewer all-cause MCI cases in Hispanic participants (Hispanic odds ratio [OR]: 1.114; NHW OR: 1.453), and APOEε2 (Hispanic OR: 1.224; NHW OR: 0.592) and depression (Hispanic OR: 2.817; NHW OR: 1.847) were associated with more AD cases in Hispanic participants. DISCUSSION: APOEε2 may not be protective for AD in Hispanic participants and Hispanic participants with depression may face a higher risk for AD. HIGHLIGHTS: GAAIN allows for discovery of data sets to use in secondary analyses. APOEε2 was not protective for AD in Hispanic participants. APOEε4 was associated with fewer MCI cases in Hispanic participants. Depression was associated with more AD cases in Hispanic participants.


Assuntos
Doença de Alzheimer , Apolipoproteínas E , Disfunção Cognitiva , Hispânico ou Latino , População Branca , Humanos , Envelhecimento , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteína E2/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/genética , Hispânico ou Latino/genética , Hispânico ou Latino/psicologia , Hispânico ou Latino/estatística & dados numéricos , Fatores de Risco , População Branca/genética , População Branca/psicologia , População Branca/estatística & dados numéricos
3.
Nat Commun ; 12(1): 4344, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272393

RESUMO

Poised enhancers (PEs) represent a genetically distinct set of distal regulatory elements that control the expression of major developmental genes. Before becoming activated in differentiating cells, PEs are already bookmarked in pluripotent cells with unique chromatin and topological features that could contribute to their privileged regulatory properties. However, since PEs were originally characterized in embryonic stem cells (ESC), it is currently unknown whether PEs are functionally conserved in vivo. Here, we show that the chromatin and 3D structural features of PEs are conserved among mouse pluripotent cells both in vitro and in vivo. We also uncovered that the interactions between PEs and their target genes are globally controlled by the combined action of Polycomb, Trithorax and architectural proteins. Moreover, distal regulatory sequences located close to developmental genes and displaying the typical genetic (i.e. CpG islands) and chromatin (i.e. high accessibility and H3K27me3 levels) features of PEs are commonly found across vertebrates. These putative PEs show high sequence conservation within specific vertebrate clades, with only a few being evolutionary conserved across all vertebrates. Lastly, by genetically disrupting PEs in mouse and chicken embryos, we demonstrate that these regulatory elements play essential roles during the induction of major developmental genes in vivo.


Assuntos
Cromatina/metabolismo , Células-Tronco Embrionárias/metabolismo , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica no Desenvolvimento/genética , Histonas/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Embrião de Galinha , Cromatina/genética , Sequenciamento de Cromatina por Imunoprecipitação , Ilhas de CpG , Células-Tronco Embrionárias/efeitos dos fármacos , Epigênese Genética , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Camadas Germinativas/metabolismo , Homozigoto , Camundongos , Filogenia , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/metabolismo , Fatores de Transcrição/genética
4.
J Vis Exp ; (141)2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30474633

RESUMO

The post-implantation mouse embryo undergoes major shape changes after the initiation of gastrulation and morphogenesis. A hallmark of morphogenesis is the formation of the transient organizers, the node and notochordal plate, from cells that have passed through the primitive streak. The proper formation of these signaling centers is essential for the development of the body plan and techniques to visualize them are of high interest to mouse developmental biologists. The node and notochordal plate lie on the ventral surface of gastrulating mouse embryos around embryonic day (E) 7.5 of development. The node is a cup-shaped structure whose cells possess a single slender cilium each. The proper subcellular localization and rotation of the cilia in the node pit determines left-right asymmetry. The notochordal plate cells also possess single cilia albeit shorter than those of the node cells. The notochordal plate forms the notochord which acts as an important signaling organizer for somitogenesis and neural patterning. Because the cells of the node and notochordal plate are transiently present on the surface and possess cilia, they can be visualized using scanning electron microscopy (SEM). Among other techniques used to visualize these structures at the cellular level is whole mount immunofluorescence (WMIF) using the antibodies against the proteins that are highly expressed in the node and notochordal plate. In this report, we describe our optimized protocols to perform SEM and WMIF of the node and notochordal plate in developing mouse embryos to help in the assessment of tissue shape and cellular organization in wild-type and gastrulation mutant embryos.


Assuntos
Desenvolvimento Embrionário/genética , Imunofluorescência/métodos , Gastrulação/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Microscopia Eletrônica de Varredura/métodos , Notocorda/crescimento & desenvolvimento , Animais , Camundongos
5.
Cancer Med ; 6(1): 220-234, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27878981

RESUMO

Because tumor cell motility is a requirement for metastasis, we hypothesized that lung tissue harbors substances that induce tumor cell migration. MCF-7 breast carcinoma cells exposed to small airway epithelial cells and conditioned medium exhibited dose-dependent tumor cell migration. Among the extracellular matrix proteins in the conditioned medium identified by mass spectrometry, laminin 332 (LM332) had the greatest contribution to the migration of MCF-7 cells. Immunoblotting and immunohistochemistry for LM332-specific chains identified LM332 in the lung and in pulmonary epithelial cells. Antibodies to either LM332 or its integrin receptor inhibited MCF-7 motility, and knockdown of LM332 chains also reduced its migration-inducing activity. Taken together, these findings implicate LM332 as a component of lung tissue that can induce motility in breast carcinoma cells that have been transported to lung during metastasis. Earlier studies on LM332 in tumor progression have examined LM332 expression in tumor cells. This investigation, in comparison, provides evidence that the tumor promoting potential of LM332 may originate in the lung microenvironment rather than in tumor cells alone. Furthermore, this study provides evidence that the motility-inducing properties of the microenvironment can reside in epithelial cells. The findings raise the possibility that LM332 plays a role in the pulmonary metastases of breast carcinoma and may provide a target for antimetastasis therapy.


Assuntos
Neoplasias da Mama/metabolismo , Moléculas de Adesão Celular/metabolismo , Células Epiteliais/citologia , Pulmão/citologia , Linhagem Celular Tumoral , Movimento Celular , Técnicas de Cocultura , Meios de Cultivo Condicionados/análise , Feminino , Humanos , Pulmão/metabolismo , Células MCF-7 , Calinina
6.
Nat Commun ; 8(1): 1456, 2017 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-29129916

RESUMO

While the transcriptional network of human embryonic stem cells (hESCs) has been extensively studied, relatively little is known about how post-transcriptional modulations determine hESC function. RNA-binding proteins play central roles in RNA regulation, including translation and turnover. Here we show that the RNA-binding protein CSDE1 (cold shock domain containing E1) is highly expressed in hESCs to maintain their undifferentiated state and prevent default neural fate. Notably, loss of CSDE1 accelerates neural differentiation and potentiates neurogenesis. Conversely, ectopic expression of CSDE1 impairs neural differentiation. We find that CSDE1 post-transcriptionally modulates core components of multiple regulatory nodes of hESC identity, neuroectoderm commitment and neurogenesis. Among these key pro-neural/neuronal factors, CSDE1 binds fatty acid binding protein 7 (FABP7) and vimentin (VIM) mRNAs, as well as transcripts involved in neuron projection development regulating their stability and translation. Thus, our results uncover CSDE1 as a central post-transcriptional regulator of hESC identity and neurogenesis.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteína 7 de Ligação a Ácidos Graxos/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Placa Neural/embriologia , Neurogênese/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Vimentina/metabolismo , Animais , Linhagem Celular , Proteínas de Ligação a DNA/genética , Proteína 7 de Ligação a Ácidos Graxos/genética , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Sistema Nervoso/embriologia , Placa Neural/citologia , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Interferência de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/genética , Proteínas Supressoras de Tumor/genética , Vimentina/genética
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