Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Dev Cell ; 59(1): 91-107.e6, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38091997

RESUMO

Genomic regulation of cardiomyocyte differentiation is central to heart development and function. This study uses genetic loss-of-function human-induced pluripotent stem cell-derived cardiomyocytes to evaluate the genomic regulatory basis of the non-DNA-binding homeodomain protein HOPX. We show that HOPX interacts with and controls cardiac genes and enhancer networks associated with diverse aspects of heart development. Using perturbation studies in vitro, we define how upstream cell growth and proliferation control HOPX transcription to regulate cardiac gene programs. We then use cell, organoid, and zebrafish regeneration models to demonstrate that HOPX-regulated gene programs control cardiomyocyte function in development and disease. Collectively, this study mechanistically links cell signaling pathways as upstream regulators of HOPX transcription to control gene programs underpinning cardiomyocyte identity and function.


Assuntos
Células-Tronco Pluripotentes Induzidas , Miócitos Cardíacos , Animais , Humanos , Miócitos Cardíacos/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Peixe-Zebra/metabolismo , Diferenciação Celular/genética , Proliferação de Células
2.
Development ; 145(12)2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29752386

RESUMO

Atrial natriuretic peptide (nppa/anf) and brain natriuretic peptide (nppb/bnp) form a gene cluster with expression in the chambers of the developing heart. Despite restricted expression, a function in cardiac development has not been demonstrated by mutant analysis. This is attributed to functional redundancy; however, their genomic location in cis has impeded formal analysis. Using genome editing, we have generated mutants for nppa and nppb, and found that single mutants were indistinguishable from wild type, whereas nppa/nppb double mutants displayed heart morphogenesis defects and pericardial oedema. Analysis of atrioventricular canal (AVC) markers show expansion of bmp4, tbx2b, has2 and versican expression into the atrium of double mutants. This expanded expression correlates with increased extracellular matrix in the atrium. Using a biosensor for hyaluronic acid to measure the cardiac jelly (cardiac extracellular matrix), we confirmed cardiac jelly expansion in nppa/nppb double mutants. Finally, bmp4 knockdown rescued the expansion of has2 expression and cardiac jelly in double mutants. This definitively shows that nppa and nppb function redundantly during cardiac development to restrict gene expression to the AVC, preventing excessive cardiac jelly synthesis in the atrial chamber.


Assuntos
Fator Natriurético Atrial/genética , Coração/embriologia , Peptídeo Natriurético Encefálico/genética , Receptores do Fator Natriurético Atrial/genética , Peixe-Zebra/embriologia , Animais , Animais Geneticamente Modificados , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Edição de Genes , Cardiopatias Congênitas/genética , Hialuronan Sintases/metabolismo , Proteínas com Domínio T/metabolismo , Versicanas/metabolismo , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
4.
Dev Cell ; 40(2): 123-136, 2017 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-28118600

RESUMO

Angiogenesis is responsible for tissue vascularization during development, as well as in pathological contexts, including cancer and ischemia. Vascular endothelial growth factors (VEGFs) regulate angiogenesis by acting through VEGF receptors to induce endothelial cell signaling. VEGF is processed in the extracellular matrix (ECM), but the complexity of ECM control of VEGF signaling and angiogenesis remains far from understood. In a forward genetic screen, we identified angiogenesis defects in tmem2 zebrafish mutants that lack both arterial and venous Vegf/Vegfr/Erk signaling. Strikingly, tmem2 mutants display increased hyaluronic acid (HA) surrounding developing vessels. Angiogenesis in tmem2 mutants was rescued, or restored after failed sprouting, by degrading this increased HA. Furthermore, oligomerized HA or overexpression of Vegfc rescued angiogenesis in tmem2 mutants. Based on these data, and the known structure of Tmem2, we find that Tmem2 regulates HA turnover to promote normal Vegf signaling during developmental angiogenesis.


Assuntos
Embrião não Mamífero/metabolismo , Ácido Hialurônico/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Animais , Artérias/metabolismo , Células Endoteliais/metabolismo , Proteínas de Membrana/química , Mutação/genética , Neovascularização Fisiológica , Fenótipo , Polimerização , Tronco/irrigação sanguínea , Veias/metabolismo , Proteínas de Peixe-Zebra/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...