Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Pharmaceuticals (Basel) ; 17(3)2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38543122

RESUMO

Heart disease is a pressing public health problem and the leading cause of death worldwide. The heart is the first organ to gain function during embryogenesis in mammals. Heart development involves cell determination, expansion, migration, and crosstalk, which are orchestrated by numerous signaling pathways, such as the Wnt, TGF-ß, IGF, and Retinoic acid signaling pathways. Human-induced pluripotent stem cell-based platforms are emerging as promising approaches for modeling heart disease in vitro. Understanding the signaling pathways that are essential for cardiac development has shed light on the molecular mechanisms of congenital heart defects and postnatal heart diseases, significantly advancing stem cell-based platforms to model heart diseases. This review summarizes signaling pathways that are crucial for heart development and discusses how these findings improve the strategies for modeling human heart disease in vitro.

2.
Nat Genet ; 55(6): 1034-1047, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37277650

RESUMO

Down syndrome (DS), the genetic condition caused by trisomy 21, is characterized by variable cognitive impairment, immune dysregulation, dysmorphogenesis and increased prevalence of diverse co-occurring conditions. The mechanisms by which trisomy 21 causes these effects remain largely unknown. We demonstrate that triplication of the interferon receptor (IFNR) gene cluster on chromosome 21 is necessary for multiple phenotypes in a mouse model of DS. Whole-blood transcriptome analysis demonstrated that IFNR overexpression associates with chronic interferon hyperactivity and inflammation in people with DS. To define the contribution of this locus to DS phenotypes, we used genome editing to correct its copy number in a mouse model of DS, which normalized antiviral responses, prevented heart malformations, ameliorated developmental delays, improved cognition and attenuated craniofacial anomalies. Triplication of the Ifnr locus modulates hallmarks of DS in mice, suggesting that trisomy 21 elicits an interferonopathy potentially amenable to therapeutic intervention.


Assuntos
Síndrome de Down , Cardiopatias Congênitas , Animais , Camundongos , Síndrome de Down/genética , Receptores de Interferon/genética , Interferons , Fenótipo , Modelos Animais de Doenças
3.
iScience ; 26(7): 107012, 2023 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-37360690

RESUMO

Congenital heart defects (CHDs) are frequent in children with Down syndrome (DS), caused by trisomy of chromosome 21. However, the underlying mechanisms are poorly understood. Here, using a human-induced pluripotent stem cell (iPSC)-based model and the Dp(16)1Yey/+ (Dp16) mouse model of DS, we identified downregulation of canonical Wnt signaling downstream of increased dosage of interferon (IFN) receptors (IFNRs) genes on chromosome 21 as a causative factor of cardiogenic dysregulation in DS. We differentiated human iPSCs derived from individuals with DS and CHDs, and healthy euploid controls into cardiac cells. We observed that T21 upregulates IFN signaling, downregulates the canonical WNT pathway, and impairs cardiac differentiation. Furthermore, genetic and pharmacological normalization of IFN signaling restored canonical WNT signaling and rescued defects in cardiogenesis in DS in vitro and in vivo. Our findings provide insights into mechanisms underlying abnormal cardiogenesis in DS, ultimately aiding the development of therapeutic strategies.

4.
J Mol Cell Cardiol ; 180: 84-93, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36965699

RESUMO

Myocardial infarction causes the loss of cardiomyocytes and the formation of cardiac fibrosis due to the activation of cardiac fibroblasts, leading to cardiac dysfunction and heart failure. Unfortunately, current therapeutic interventions can only slow the disease progression. Furthermore, they cannot fully restore cardiac function, likely because the adult human heart lacks sufficient capacity to regenerate cardiomyocytes. Therefore, intensive efforts have focused on developing therapeutics to regenerate the damaged heart. Several strategies have been intensively investigated, including stimulation of cardiomyocyte proliferation, transplantation of stem cell-derived cardiomyocytes, and conversion of fibroblasts into cardiac cells. Resident cardiac fibroblasts are critical in the maintenance of the structure and contractility of the heart. Fibroblast plasticity makes this type of cells be reprogrammed into many cell types, including but not limited to induced pluripotent stem cells, induced cardiac progenitor cells, and induced cardiomyocytes. Fibroblasts have become a therapeutic target due to their critical roles in cardiac pathogenesis. This review summarizes the reprogramming of fibroblasts into induced pluripotent stem cell-derived cardiomyocytes, induced cardiac progenitor cells, and induced cardiomyocytes to repair a damaged heart, outlines recent findings in utilizing fibroblast-derived cells for heart regeneration, and discusses the limitations and challenges.


Assuntos
Cardiopatias , Células-Tronco Pluripotentes Induzidas , Humanos , Reprogramação Celular , Miócitos Cardíacos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Cardiopatias/patologia , Fibroblastos/metabolismo
5.
Sci Adv ; 9(3): eade8346, 2023 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-36662855

RESUMO

Malfunction of the sialic acid transporter caused by various genetic mutations in the SLC17A5 gene encoding Sialin leads to a spectrum of neurodegenerative conditions called free sialic acid storage disorders. Unfortunately, how Sialin transports sialic acid/proton (H+) and how pathogenic mutations impair its function are poorly defined. Here, we present the structure of human Sialin in an inward-facing partially open conformation determined by cryo-electron microscopy, representing the first high-resolution structure of any human SLC17 member. Our analysis reveals two unique features in Sialin: (i) The H+ coupling/sensing requires two highly conserved Glu residues (E171 and E175) instead of one (E175) as implied in previous studies; and (ii) the normal function of Sialin requires the stabilization of a cytosolic helix, which has not been noticed in the literature. By mapping known pathogenic mutations, we provide mechanistic explanations for corresponding functional defects. We propose a structure-based mechanism for sialic acid transport mediated by Sialin.


Assuntos
Doença do Armazenamento de Ácido Siálico , Simportadores , Humanos , Ácido N-Acetilneuramínico , Microscopia Crioeletrônica , Doença do Armazenamento de Ácido Siálico/genética , Mutação , Simportadores/genética , Simportadores/metabolismo , Transporte de Íons
6.
Circulation ; 146(9): 699-714, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-35862102

RESUMO

BACKGROUND: Abnormalities in Ca2+ homeostasis are associated with cardiac arrhythmias and heart failure. Triadin plays an important role in Ca2+ homeostasis in cardiomyocytes. Alternative splicing of a single triadin gene produces multiple triadin isoforms. The cardiac-predominant isoform, mouse MT-1 or human Trisk32, is encoded by triadin exons 1 to 8. In humans, mutations in the triadin gene that lead to a reduction in Trisk32 levels in the heart can cause cardiac dysfunction and arrhythmias. Decreased levels of Trisk32 in the heart are also common in patients with heart failure. However, mechanisms that maintain triadin isoform composition in the heart remain elusive. METHODS: We analyzed triadin expression in heart explants from patients with heart failure and cardiac arrhythmias and in hearts from mice carrying a knockout allele for Trdn-as, a cardiomyocyte-specific long noncoding RNA encoded by the antisense strand of the triadin gene, between exons 9 and 11. Catecholamine challenge with isoproterenol was performed on Trdn-as knockout mice to assess the role of Trdn-as in cardiac arrhythmogenesis, as assessed by ECG. Ca2+ transients in adult mouse cardiomyocytes were measured with the IonOptix platform or the GCaMP system. Biochemistry assays, single-molecule fluorescence in situ hybridization, subcellular localization imaging, RNA sequencing, and molecular rescue assays were used to investigate the mechanisms by which Trdn-as regulates cardiac function and triadin levels in the heart. RESULTS: We report that Trdn-as maintains cardiac function, at least in part, by regulating alternative splicing of the triadin gene. Knockout of Trdn-as in mice downregulates cardiac triadin, impairs Ca2+ handling, and causes premature death. Trdn-as knockout mice are susceptible to cardiac arrhythmias in response to catecholamine challenge. Normalization of cardiac triadin levels in Trdn-as knockout cardiomyocytes is sufficient to restore Ca2+ handling. Last, Trdn-as colocalizes and interacts with serine/arginine splicing factors in cardiomyocyte nuclei and is essential for efficient recruitment of splicing factors to triadin precursor mRNA. CONCLUSIONS: These findings reveal regulation of alternative splicing as a novel mechanism by which a long noncoding RNA controls cardiac function. This study indicates potential therapeutics for heart disease by targeting the long noncoding RNA or pathways regulating alternative splicing.


Assuntos
Processamento Alternativo , Proteínas de Transporte , Insuficiência Cardíaca , Proteínas Musculares , RNA Longo não Codificante , Animais , Arritmias Cardíacas , Proteínas de Transporte/genética , Catecolaminas , Coração/fisiologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Humanos , Hibridização in Situ Fluorescente , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Knockout , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Miócitos Cardíacos/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , RNA Longo não Codificante/genética
7.
Stem Cell Reports ; 16(3): 519-533, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33636116

RESUMO

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful platform for biomedical research. However, they are immature, which is a barrier to modeling adult-onset cardiovascular disease. Here, we sought to develop a simple method that could drive cultured hiPSC-CMs toward maturity across a number of phenotypes, with the aim of utilizing mature hiPSC-CMs to model human cardiovascular disease. hiPSC-CMs were cultured in fatty acid-based medium and plated on micropatterned surfaces. These cells display many characteristics of adult human cardiomyocytes, including elongated cell morphology, sarcomeric maturity, and increased myofibril contractile force. In addition, mature hiPSC-CMs develop pathological hypertrophy, with associated myofibril relaxation defects, in response to either a pro-hypertrophic agent or genetic mutations. The more mature hiPSC-CMs produced by these methods could serve as a useful in vitro platform for characterizing cardiovascular disease.


Assuntos
Cardiomiopatia Hipertrófica/fisiopatologia , Técnicas de Cultura de Células/métodos , Diferenciação Celular , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células-Tronco Pluripotentes Induzidas/fisiologia , Miócitos Cardíacos/fisiologia , Linhagem Celular , Células Cultivadas , Meios de Cultura/química , Ácidos Graxos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Modelos Biológicos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miofibrilas/fisiologia , Fenilefrina/farmacologia , Sarcômeros/fisiologia , Análise de Sequência de RNA , Transdução de Sinais
8.
J Mol Cell Cardiol ; 153: 44-59, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33359755

RESUMO

Direct reprogramming of fibroblasts into cardiomyocytes (CMs) represents a promising strategy to regenerate CMs lost after ischemic heart injury. Overexpression of GATA4, HAND2, MEF2C, TBX5, miR-1, and miR-133 (GHMT2m) along with transforming growth factor beta (TGF-ß) inhibition efficiently promote reprogramming. However, the mechanisms by which TGF-ß blockade promotes cardiac reprogramming remain unknown. Here, we identify interactions between the histone H3 lysine 27 trimethylation (H3K27me3) demethylase JMJD3, the SWI/SNF remodeling complex subunit BRG1, and cardiac transcription factors. Furthermore, canonical TGF-ß signaling regulates the interaction between GATA4 and JMJD3. TGF-ß activation impairs the ability of GATA4 to bind target genes and prevents demethylation of H3K27 at cardiac gene promoters during cardiac reprogramming. Finally, a mutation in GATA4 (V267M) that is associated with congenital heart disease exhibits reduced binding to JMJD3 and impairs cardiomyogenesis. Thus, we have identified an epigenetic mechanism wherein canonical TGF-ß pathway activation impairs cardiac gene programming, in part by interfering with GATA4-JMJD3 interactions.


Assuntos
Fator de Transcrição GATA4/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Pluripotentes Induzidas/citologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Miócitos Cardíacos/citologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Metilação de DNA , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Fator de Transcrição GATA4/genética , Histonas/química , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo
9.
Int J Mol Sci ; 21(3)2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32012649

RESUMO

The lysosome, a key organelle for cellular clearance, is associated with a wide variety of pathological conditions in humans. Lysosome function and its related pathways are particularly important for maintaining the health of the cardiovascular system. In this review, we highlighted studies that have improved our understanding of the connection between lysosome function and cardiovascular diseases with an emphasis on a recent breakthrough that characterized a unique autophagosome-lysosome fusion mechanism employed by cardiomyocytes through a lysosomal membrane protein LAMP-2B. This finding may impact the development of future therapeutic applications.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Suscetibilidade a Doenças , Lisossomos/metabolismo , Animais , Autofagossomos/metabolismo , Autofagia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Gerenciamento Clínico , Predisposição Genética para Doença , Terapia Genética , Doença de Depósito de Glicogênio Tipo IIb/diagnóstico , Doença de Depósito de Glicogênio Tipo IIb/etiologia , Doença de Depósito de Glicogênio Tipo IIb/metabolismo , Humanos , Proteína 2 de Membrana Associada ao Lisossomo/genética , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Fusão de Membrana , Proteínas de Membrana , Mutação , Miócitos Cardíacos/metabolismo , Fenótipo
10.
Cell Rep ; 30(6): 1848-1861.e5, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32049015

RESUMO

Nucleotide deprivation and imbalance present detrimental conditions for animals and are thus expected to trigger cellular responses that direct protective changes in metabolic, developmental, and behavioral programs, albeit such mechanisms are vastly underexplored. Following our previous finding that Caenorhabditis elegans shut down germ cell proliferation in response to pyrimidine deprivation, we find in this study that endonuclease ENDU-2 regulates nucleotide metabolism and germ cell proliferation in response to nucleotide imbalance and other genotoxic stress, and that it affects mitotic chromosomal segregation in the intestine and lifespan. ENDU-2 expression is induced by nucleotide imbalance and genotoxic stress, and ENDU-2 exerts its function in the intestine, mostly by inhibiting the phosphorylation of CTPS-1 through repressing the PKA pathway and histone deacetylase HDA-1. Human EndoU also affects the response to genotoxic drugs. Our work reveals an unknown role of ENDU-2 in regulating nucleotide metabolism and animals' response to genotoxic stress, which may link EndoU function to cancer treatment.


Assuntos
Dano ao DNA/fisiologia , Endonucleases/metabolismo , Células Germinativas/metabolismo , Nucleotídeos/metabolismo , Proliferação de Células , Humanos , Fosforilação , Transdução de Sinais
11.
Proc Natl Acad Sci U S A ; 116(2): 556-565, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30584088

RESUMO

Mutations in lysosomal-associated membrane protein 2 (LAMP-2) gene are associated with Danon disease, which often leads to cardiomyopathy/heart failure through poorly defined mechanisms. Here, we identify the LAMP-2 isoform B (LAMP-2B) as required for autophagosome-lysosome fusion in human cardiomyocytes (CMs). Remarkably, LAMP-2B functions independently of syntaxin 17 (STX17), a protein that is essential for autophagosome-lysosome fusion in non-CMs. Instead, LAMP-2B interacts with autophagy related 14 (ATG14) and vesicle-associated membrane protein 8 (VAMP8) through its C-terminal coiled coil domain (CCD) to promote autophagic fusion. CMs derived from induced pluripotent stem cells (hiPSC-CMs) from Danon patients exhibit decreased colocalization between ATG14 and VAMP8, profound defects in autophagic fusion, as well as mitochondrial and contractile abnormalities. This phenotype was recapitulated by LAMP-2B knockout in non-Danon hiPSC-CMs. Finally, gene correction of LAMP-2 mutation rescues the Danon phenotype. These findings reveal a STX17-independent autophagic fusion mechanism in human CMs, providing an explanation for cardiomyopathy in Danon patients and a foundation for targeting defective LAMP-2B-mediated autophagy to treat this patient population.


Assuntos
Autofagossomos/metabolismo , Doença de Depósito de Glicogênio Tipo IIb/metabolismo , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Lisossomos/metabolismo , Fusão de Membrana , Miócitos Cardíacos/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Autofagossomos/patologia , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Técnicas de Inativação de Genes , Doença de Depósito de Glicogênio Tipo IIb/genética , Doença de Depósito de Glicogênio Tipo IIb/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Proteína 2 de Membrana Associada ao Lisossomo/genética , Lisossomos/genética , Lisossomos/patologia , Miócitos Cardíacos/patologia , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/metabolismo , Proteínas R-SNARE/genética , Proteínas R-SNARE/metabolismo
12.
13.
Genes Dev ; 30(3): 307-20, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26833730

RESUMO

Animals alter their reproductive programs to accommodate changes in nutrient availability, yet the connections between known nutrient-sensing systems and reproductive programs are underexplored, and whether there is a mechanism that senses nucleotide levels to coordinate germline proliferation is unknown. We established a model system in which nucleotide metabolism is perturbed in both the nematode Caenorhabditis elegans (cytidine deaminases) and its food (Escherichia coli); when fed food with a low uridine/thymidine (U/T) level, germline proliferation is arrested. We provide evidence that this impact of U/T level on the germline is critically mediated by GLP-1/Notch and MPK-1/MAPK, known to regulate germline mitotic proliferation. This germline defect is suppressed by hyperactivation of glp-1 or disruption of genes downstream from glp-1 to promote meiosis but not by activation of the IIS or TORC1 pathways. Moreover, GLP-1 expression is post-transcriptionally modulated by U/T levels. Our results reveal a previously unknown nucleotide-sensing mechanism for controlling reproductivity.


Assuntos
Caenorhabditis elegans/fisiologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Nucleotídeos/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proliferação de Células/genética , Escherichia coli/genética , Fertilidade/genética , Células Germinativas , Mutação
14.
Dev Dyn ; 239(10): 2594-602, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20803506

RESUMO

Notch pathway has been demonstrated to regulate cardiovascular development. One important step in Notch pathway is the cleavage of Notch receptor, during which an intracellular fragment of Notch protein is released to activate downstream genes. It is still uncertain whether Adam10, the mammalian homologue of Kuzbanian in Drosophila, is required to activate the Notch pathway during cardiovascular development. To further understand the physiological function of Adam10 in vascular and cardiac development, we generated mice lacking the Adam10 gene primarily in the endothelial compartment. We found that disruption of Adam10 in endothelial cells resulted in embryonic death after embryonic day 10.5 due to multiple cardiac and vascular defects similar to Notch1 mutants. We further showed that the expression of Notch target genes Snail and Bmp2 are impaired in Adam10-deficient cardiac tissues. Finally, we provide experimental evidence to support that Adam10 functions in a cell autonomous manner during mammalian cardiac development.


Assuntos
Proteínas ADAM/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Sistema Cardiovascular/embriologia , Proteínas de Membrana/metabolismo , Proteínas ADAM/genética , Proteína ADAM10 , Secretases da Proteína Precursora do Amiloide/genética , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Transição Epitelial-Mesenquimal , Imuno-Histoquímica , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Receptor Notch1/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
15.
J Biol Chem ; 285(28): 21817-23, 2010 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-20418542

RESUMO

Lysosome function is essential to many physiological processes. It has been suggested that deregulation of lysosome function could contribute to cancer. Through a genetic screen in Drosophila, we have discovered that mutations disrupting lysosomal degradation pathway components contribute to tumor development and progression. Loss-of-function mutations in the Class C vacuolar protein sorting (VPS) gene, deep orange (dor), dramatically promote tumor overgrowth and invasion of the Ras(V12) cells. Knocking down either of the two other components of the Class C VPS complex, carnation (car) and vps16A, also renders Ras(V12) cells capable for uncontrolled growth and metastatic behavior. Finally, chemical disruption of the lysosomal function by feeding animals with antimalarial drugs, chloroquine or monensin, leads to malignant tumor growth of the Ras(V12) cells. Taken together, our data provide evidence for a causative role of lysosome dysfunction in tumor growth and invasion and indicate that members of the Class C VPS complex behave as tumor suppressors.


Assuntos
Drosophila/genética , Lisossomos/metabolismo , Metástase Neoplásica , Neoplasias/patologia , Animais , Cloroquina/química , Cruzamentos Genéticos , Genótipo , Proteínas de Fluorescência Verde/química , Humanos , Modelos Genéticos , Monensin/química , Neoplasias/genética , Interferência de RNA , Proteínas de Transporte Vesicular/metabolismo , Proteínas ras/metabolismo
16.
Int Immunol ; 20(9): 1181-7, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18635581

RESUMO

Notch signaling pathway has been shown to play essential roles in T lymphocyte development. Activation of Notch requires a sequential proteolytic cleavage, which converts Notch from the full-length membrane-bound form to a transcriptionally active intracellular fragment. Studies in Drosophila showed that Kuzbanian (Kuz) is responsible for the enzymatic cleavage of extracellular S2 site upon Notch binding to its ligand Delta. Both a disintegrin and metalloprotease (ADAM) 10 and ADAM17, members of the ADAM family metalloproteases, have been indicated as the mammalian counterpart of Kuz in activating Notch in mammals. Here, we investigated functions of ADAM10 in Notch signaling during thymocyte development. We show that conditional disruption of the Adam10 gene in mouse thymocytes results in a developmental defect similar to the phenotypes previously described for T lineage-specific disruption of Notch1. We further show that the activation of Notch1 and its downstream target genes Deltex-1 and Pre-Ta are impaired in Adam10-deficient thymocytes. Our study demonstrates a T cell intrinsic role for Adam10 in activation of Notch1 during thymocyte development.


Assuntos
Proteínas ADAM/metabolismo , Regulação da Expressão Gênica , Receptor Notch1/metabolismo , Linfócitos T/citologia , Proteínas ADAM/genética , Animais , Diferenciação Celular , Citometria de Fluxo , Linfopoese , Camundongos , Camundongos Knockout , Receptor Notch1/genética , Linfócitos T/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...