Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 15 de 15
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nature ; 571(7763): 107-111, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31217582

RESUMO

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.


Assuntos
Diarreia/congênito , Diarreia/genética , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes , Intestinos/fisiologia , Deleção de Sequência/genética , Animais , Cromossomos Humanos Par 16/genética , Modelos Animais de Doenças , Feminino , Genes Reporter , Loci Gênicos/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Linhagem , Fenótipo , Ativação Transcricional , Transcriptoma/genética , Transgenes/genética
2.
Dev Biol ; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30521808

RESUMO

MEF2C is a member of the highly conserved MEF2 family of transcription factors and is a key regulator of cardiovascular development. In mice, Mef2c is expressed in the developing heart and vasculature, including the endothelium. Loss of Mef2c function in germline knockout mice leads to early embryonic demise and profound developmental abnormalities in the cardiovascular system. Previous attempts to uncover the cause of embryonic lethality by specifically disrupting Mef2c function in the heart or vasculature failed to recapitulate the global Mef2c knockout phenotype and instead resulted in relatively minor defects that did not compromise viability or result in significant cardiovascular defects. However, previous studies examined the requirement of Mef2c in the myocardial and endothelial lineages using Cre lines that begin to be expressed after the expression of Mef2c has already commenced. Here, we tested the requirement of Mef2c in the myocardial and endothelial lineages using conditional knockout approaches in mice with Cre lines that deleted Mef2c prior to onset of its expression in embryonic development. We found that deletion of Mef2c in the early myocardial lineage using Nkx2-5Cre resulted in cardiac and vascular abnormalities that were indistinguishable from the defects in the global Mef2c knockout. In contrast, early deletion of Mef2c in the vascular endothelium using an Etv2::Cre line active prior to the onset of Mef2c expression resulted in viable offspring that were indistinguishable from wild type controls with no overt defects in vascular development, despite nearly complete early deletion of Mef2c in the vascular endothelium. Thus, these studies support the idea that the requirement of MEF2C for vascular development is secondary to its requirement in the heart and suggest that the observed failure in vascular remodeling in Mef2c knockout mice results from defective heart function.

3.
Proc Natl Acad Sci U S A ; 113(27): 7563-8, 2016 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-27335460

RESUMO

Cranial neural crest cells (crNCCs) migrate from the neural tube to the pharyngeal arches (PAs) of the developing embryo and, subsequently, differentiate into bone and connective tissue to form the mandible. Within the PAs, crNCCs respond to local signaling cues to partition into the proximo-distally oriented subdomains that convey positional information to these developing tissues. Here, we show that the distal-most of these subdomains, the distal cap, is marked by expression of the transcription factor Hand1 (H1) and gives rise to the ectomesenchymal derivatives of the lower incisors. We uncover a H1 enhancer sufficient to drive reporter gene expression within the crNCCs of the distal cap. We show that bone morphogenic protein (BMP) signaling and the transcription factor HAND2 (H2) synergistically regulate H1 distal cap expression. Furthermore, the homeodomain proteins distal-less homeobox 5 (DLX5) and DLX6 reciprocally inhibit BMP/H2-mediated H1 enhancer regulation. These findings provide insights into how multiple signaling pathways direct transcriptional outcomes that pattern the developing jaw.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas de Homeodomínio/metabolismo , Mandíbula/embriologia , Animais , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Elementos Facilitadores Genéticos , Fatores de Transcrição GATA/metabolismo , Genes Reporter , Mandíbula/metabolismo , Camundongos Transgênicos , Dados de Sequência Molecular , Proteínas Smad/metabolismo
4.
Development ; 143(5): 774-9, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26811383

RESUMO

Congenital heart defects are the most common birth defects in humans, and those that affect the proper alignment of the outflow tracts and septation of the ventricles are a highly significant cause of morbidity and mortality in infants. A late differentiating population of cardiac progenitors, referred to as the anterior second heart field (AHF), gives rise to the outflow tract and the majority of the right ventricle and provides an embryological context for understanding cardiac outflow tract alignment and membranous ventricular septal defects. However, the transcriptional pathways controlling AHF development and their roles in congenital heart defects remain incompletely elucidated. Here, we inactivated the gene encoding the transcription factor MEF2C in the AHF in mice. Loss of Mef2c function in the AHF results in a spectrum of outflow tract alignment defects ranging from overriding aorta to double-outlet right ventricle and dextro-transposition of the great arteries. We identify Tdgf1, which encodes a Nodal co-receptor (also known as Cripto), as a direct transcriptional target of MEF2C in the outflow tract via an AHF-restricted Tdgf1 enhancer. Importantly, both the MEF2C and TDGF1 genes are associated with congenital heart defects in humans. Thus, these studies establish a direct transcriptional pathway between the core cardiac transcription factor MEF2C and the human congenital heart disease gene TDGF1. Moreover, we found a range of outflow tract alignment defects resulting from a single genetic lesion, supporting the idea that AHF-derived outflow tract alignment defects may constitute an embryological spectrum rather than distinct anomalies.


Assuntos
Fator de Crescimento Epidérmico/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Glicoproteínas de Membrana/fisiologia , Proteínas de Neoplasias/fisiologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Fator de Crescimento Epidérmico/genética , Feminino , Deleção de Genes , Coração/embriologia , Cardiopatias Congênitas/genética , Comunicação Interventricular/genética , Ventrículos do Coração , Humanos , Hibridização In Situ , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/fisiologia , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Morfogênese/genética , Proteínas de Neoplasias/genética , Organogênese , Análise de Sequência de RNA , Distribuição Tecidual , Transcrição Genética , Transposição dos Grandes Vasos/genética
5.
Skelet Muscle ; 5: 7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25789156

RESUMO

BACKGROUND: Skeletal muscle is the most abundant tissue in the body and is a major source of total energy expenditure in mammals. Skeletal muscle consists of fast and slow fiber types, which differ in their energy usage, contractile speed, and force generation. Although skeletal muscle plays a major role in whole body metabolism, the transcription factors controlling metabolic function in muscle remain incompletely understood. Members of the myocyte enhancer factor 2 (MEF2) family of transcription factors play crucial roles in skeletal muscle development and function. MEF2C is expressed in skeletal muscle during development and postnatally and is known to play roles in sarcomeric gene expression, fiber type control, and regulation of metabolic genes. METHODS: We generated mice lacking Mef2c exclusively in skeletal muscle using a conditional knockout approach and conducted a detailed phenotypic analysis. RESULTS: Mice lacking Mef2c in skeletal muscle on an outbred background are viable and grow to adulthood, but they are significantly smaller in overall body size compared to control mice and have significantly fewer slow fibers. When exercised in a voluntary wheel running assay, Mef2c skeletal muscle knockout mice aberrantly accumulate glycogen in their muscle, suggesting an impairment in normal glucose homeostasis. Consistent with this notion, Mef2c skeletal muscle knockout mice exhibit accelerated blood glucose clearance compared to control mice. CONCLUSIONS: These findings demonstrate that MEF2C function in skeletal muscle is important for metabolic homeostasis and control of overall body size.

6.
Dev Biol ; 395(2): 379-389, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25179465

RESUMO

Endothelin-converting enzyme-1 (Ece-1), a crucial component of the Endothelin signaling pathway, is required for embryonic development and is an important regulator of vascular tone, yet the transcriptional regulation of the ECE1 gene has remained largely unknown. Here, we define the activity and regulation of an enhancer from the human ECE1 locus in vivo. The enhancer identified here becomes active in endothelial progenitor cells shortly after their initial specification and is dependent on a conserved FOX:ETS motif, a composite binding site for Forkhead transcription factors and the Ets transcription factor Etv2, for activity in vivo. The ECE1 FOX:ETS motif is bound and cooperatively activated by FoxC2 and Etv2, but unlike other described FOX:ETS-dependent enhancers, ECE1 enhancer activity becomes restricted to arterial endothelium and endocardium by embryonic day 9.5 in transgenic mouse embryos. The ECE1 endothelial enhancer also contains an evolutionarily-conserved, consensus SOX binding site, which is required for activity in transgenic mouse embryos. Importantly, the ECE1 SOX site is bound and activated by Sox17, a transcription factor involved in endothelial cell differentiation and an important regulator of arterial identity. Moreover, the ECE1 enhancer is cooperatively activated by the combinatorial action of FoxC2, Etv2, and Sox17. Although Sox17 is required for arterial identity, few direct transcriptional targets have been identified in endothelial cells. Thus, this work has important implications for our understanding of endothelial specification and arterial subspecification.


Assuntos
Ácido Aspártico Endopeptidases/metabolismo , Endocárdio/embriologia , Endotélio Vascular/embriologia , Fatores de Transcrição Forkhead/metabolismo , Metaloendopeptidases/metabolismo , Fatores de Transcrição SOXF/metabolismo , Fatores de Transcrição/metabolismo , Animais , Ácido Aspártico Endopeptidases/genética , Clonagem Molecular , Primers do DNA/genética , Ensaio de Desvio de Mobilidade Eletroforética , Endocárdio/metabolismo , Enzimas Conversoras de Endotelina , Endotélio Vascular/metabolismo , Elementos Facilitadores Genéticos/genética , Imunofluorescência , Galactosídeos , Humanos , Indóis , Metaloendopeptidases/genética , Camundongos , Camundongos Transgênicos , Mutagênese , Fatores de Transcrição SOX/metabolismo
7.
Dev Biol ; 393(2): 245-254, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25050930

RESUMO

Coordinated contraction of the heart is essential for survival and is regulated by the cardiac conduction system. Contraction of ventricular myocytes is controlled by the terminal part of the conduction system known as the Purkinje fiber network. Lineage analyses in chickens and mice have established that the Purkinje fibers of the peripheral ventricular conduction system arise from working myocytes during cardiac development. It has been proposed, based primarily on gain-of-function studies, that Endothelin signaling is responsible for myocyte-to-Purkinje fiber transdifferentiation during avian heart development. However, the role of Endothelin signaling in mammalian conduction system development is less clear, and the development of the cardiac conduction system in mice lacking Endothelin signaling has not been previously addressed. Here, we assessed the specification of the cardiac conduction system in mouse embryos lacking all Endothelin signaling. We found that mouse embryos that were homozygous null for both ednra and ednrb, the genes encoding the two Endothelin receptors in mice, were born at predicted Mendelian frequency and had normal specification of the cardiac conduction system and apparently normal electrocardiograms with normal QRS intervals. In addition, we found that ednra expression within the heart was restricted to the myocardium while ednrb expression in the heart was restricted to the endocardium and coronary endothelium. By establishing that ednra and ednrb are expressed in distinct compartments within the developing mammalian heart and that Endothelin signaling is dispensable for specification and function of the cardiac conduction system, this work has important implications for our understanding of mammalian cardiac development.


Assuntos
Endotelinas/metabolismo , Contração Miocárdica/fisiologia , Ramos Subendocárdicos/embriologia , Receptores de Endotelina/genética , Animais , Diferenciação Celular , Transdiferenciação Celular , Conexina 43/biossíntese , Conexinas/biossíntese , Endocárdio/metabolismo , Endotélio/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Organogênese , Ramos Subendocárdicos/fisiologia , Receptores de Endotelina/biossíntese , Transdução de Sinais
8.
Birth Defects Res A Clin Mol Teratol ; 91(6): 485-94, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21462297

RESUMO

Almost 15 years of careful study have established the related basic Helix-Loop-Helix (bHLH) transcription factors Hand1 and Hand2 as critical for heart development across evolution. Hand factors make broad contributions, revealed through animal models, to the development of multiple cellular lineages that ultimately contribute to the heart. They perform critical roles in ventricular cardiomyocyte growth, differentiation, morphogenesis, and conduction. They are also important for the proper development of the cardiac outflow tract, epicardium, and endocardium. Molecularly, they function both through DNA binding and through protein-protein interactions, which are regulated transcriptionally, posttranscriptionally by microRNAs, and posttranslationally through phosphoregulation. Although direct Hand factor transcriptional targets are progressively being identified, confirmed direct targets of Hand factor transcriptional activity in the heart are limited. Identification of these targets will be critical to model the mechanisms by which Hand factor bHLH interactions affect developmental pathways. Improved understanding of Hand factor-mediated transcriptional cascades will be necessary to determine how Hand factor dysregulation translates to human disease phenotypes. This review summarizes the insight that animal models have provided into the regulation and function of these factors during heart development, in addition to the recent findings that suggest roles for HAND1 and HAND2 in human congenital heart disease.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cardiopatias Congênitas/metabolismo , Coração/embriologia , Miocárdio/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Regulação da Expressão Gênica no Desenvolvimento , Cardiopatias Congênitas/genética , Humanos , Morfogênese
9.
Circ Res ; 108(8): 940-9, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21350214

RESUMO

RATIONALE: The basic helix-loop-helix (bHLH) transcription factors Hand1 and Hand2 are essential for embryonic development. Given their requirement for cardiogenesis, it is imperative to determine their impact on cardiovascular function. OBJECTIVE: To deduce the role of Hand2 within the epicardium. METHOD AND RESULTS: We engineered a Hand1 allele expressing Cre recombinase. Cardiac Hand1 expression is largely limited to cells of the primary heart field, overlapping little with Hand2 expression. Hand1 is expressed within the septum transversum, and the Hand1 lineage marks the proepicardial organ and epicardium. To examine Hand factor functional overlap, we conditionally deleted Hand2 from Hand1-expressing cells. Hand2 mutants display defective epicardialization and fail to form coronary arteries, coincident with altered extracellular matrix deposition and Pdgfr expression. CONCLUSIONS: These data demonstrate a hierarchal relationship whereby transient Hand1 septum transversum expression defines epicardial precursors that are subsequently dependent on Hand2 function.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Vasos Coronários/embriologia , Vasos Coronários/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Pericárdio/embriologia , Pericárdio/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem da Célula/genética , Células Cultivadas , Vasos Coronários/citologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pericárdio/citologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Células-Tronco/patologia
10.
Dev Dyn ; 239(11): 3086-97, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20882677

RESUMO

The basic Helix-Loop-Helix (bHLH) transcription factors Hand1 and Hand2 play critical roles in the development of multiple organ systems during embryogenesis. The dynamic expression patterns of these two factors within developing tissues obfuscate their respective unique and redundant organogenic functions. To define cell lineages potentially dependent upon Hand gene expression, we generated a mutant allele in which the coding region of Hand1 is replaced by Cre recombinase. Subsequent Cre-mediated activation of ß-galactosidase or eYFP reporter alleles enabled lineage trace analyses that clearly define the fate of Hand1-expressing cells. Hand1-driven Cre marks specific lineages within the extra embryonic tissues, placenta, sympathetic nervous system, limbs, jaw, and several cell types within the cardiovascular system. Comparisons between Hand1 expression and Hand1-lineage greatly refine our understanding of its dynamic spatial-temporal expression domains and raise the possibility of novel Hand1 functions in structures not thought to be Hand1-dependent.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sistema Cardiovascular/metabolismo , Embrião de Mamíferos/metabolismo , Mesoderma/metabolismo , Crista Neural/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Sistema Cardiovascular/embriologia , Feminino , Genótipo , Imuno-Histoquímica , Hibridização In Situ , Masculino , Mesoderma/embriologia , Camundongos , Camundongos Knockout , Crista Neural/embriologia
11.
Dev Dyn ; 239(10): 2748-60, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20737509

RESUMO

Loss-of-function analysis of the basic helix-loop-helix (bHLH) transcription factor Hand1 indicates critical roles in development. In an effort to generate a Hand1 cDNA knock-in reporter mouse, we generated two hypomorphic alleles, which extend embryonic survival to between embryonic day (E) 10.5 and E12.5. Heart morphogenesis appears largely normal; however, hypomorphic mice display thin left ventricular myocardium and reduction in pharyngeal mesoderm. Caudal defects, large allantois, and thickened yolk sac are observed and consistent with systemic Hand1 gene deletion. Hand1 mRNA is expressed at 30% of wild-type littermates and known Hand1-dependent genes show intermediate expression compared with wild-type and Hand1 null mice. Interestingly, putative bHLH partners, Hand2 and Twist1, show altered expression in both Hand1 null and hypomorphic backgrounds and intercrossing the Hand1 hypomorphic mice onto the Hand2 systemic null background exacerbates the cardiac and lateral mesoderm phenotypes. Together, these data define a critical threshold of Hand1 expression that is necessary for embryonic survival.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Embrião de Mamíferos/metabolismo , Alelos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Coração/embriologia , Immunoblotting , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
Int J Dev Biol ; 53(7): 909-24, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19378251

RESUMO

Members of the Twist-family of bHLH proteins play a pivotal role in a number of essential developmental programs. Twist-family bHLH proteins function by dimerizing with other bHLH members and binding to cis- regulatory elements, called E-boxes. While Twist-family members may simply exhibit a preference in terms of high-affinity binding partners, a complex, multilevel cascade of regulation creates a dynamic role for these bHLH proteins. We summarize in this review information on each Twist-family member concerning expression pattern, function, regulation, downstream targets, and interactions with other bHLH proteins. Additionally, we focus on the phospho-regulatory mechanisms that tightly control posttranslational modification of Twist-family member bHLH proteins.


Assuntos
Morfogênese/fisiologia , Proteína 1 Relacionada a Twist/fisiologia , Sequência de Aminoácidos , Animais , Dimerização , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Drosophila/fisiologia , Desenvolvimento Embrionário/genética , Desenvolvimento Embrionário/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Modelos Biológicos , Dados de Sequência Molecular , Morfogênese/genética , Filogenia , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , Proteína 1 Relacionada a Twist/química , Proteína 1 Relacionada a Twist/genética , Vertebrados
14.
Dev Dyn ; 237(12): 3809-19, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19035347

RESUMO

The interactions of diverse transcription factors mediate the molecular programs that regulate mammalian heart development. Among these, Nkx2.5 and the Mef2c regulate common downstream targets and exhibit striking phenotypic similarities when disrupted, suggesting a potential interaction during heart development. Co-immunoprecipitation and mammalian two-hybrid experiments revealed a direct molecular interaction between Nkx2.5 and Mef2c. Assessment of mRNA expression verified spatiotemporal cardiac coexpression. Finally, genetic interaction studies employing histological and molecular analyses showed that, although Nkx2.5(-/-) and Mef2c(-/-) individual mutants both have identifiable ventricles, Nkx2.5(-/-);Mef2c(-/-) double mutants do not, and that mutant cardiomyocytes express only atrial and second heart field markers. Molecular marker and cell death and proliferation analyses provide evidence that ventricular hypoplasia is the result of defective ventricular cell differentiation. Collectively, these data support a hypothesis where physical, functional, and genetic interactions between Nkx2.5 and Mef2c are necessary for ventricle formation.


Assuntos
Coração/embriologia , Proteínas de Homeodomínio/imunologia , Miocárdio/metabolismo , Fatores de Regulação Miogênica/imunologia , Fatores de Transcrição/imunologia , Animais , Diferenciação Celular , Linhagem Celular , Regulação da Expressão Gênica no Desenvolvimento , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Humanos , Fatores de Transcrição MEF2 , Camundongos , Camundongos Knockout , Mutação/genética , Miocárdio/citologia , Fatores de Regulação Miogênica/genética , Ligação Proteica , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética
15.
Dev Biol ; 320(1): 131-9, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18539270

RESUMO

The basic helix-loop-helix transcription factor Twist1 plays an essential role in mesenchymal cell populations during embryonic development and in pathological disease. Remodeling of the cardiac outflow tract (OFT) into the functionally separate aortic arch and pulmonary trunk is dependent upon the dynamic, coordinated contribution of multiple mesenchymal cell populations. Here, we report that Twist1(-/-) mice exhibit OFTs that contain amorphic cellular nodules within their OFT endocardial cushions. The nodular mesenchyme expresses the related bHLH factors Hand1 and Hand2, but reduced levels of the normal cushion marker Periostin. Lineage mapping confirms that nodule cells are exclusively of cardiac neural crest origin (cNCC), and are not ectopic cardiomyocytes or smooth muscle cells. These studies also reveal a delay in cNCC colonization of the OFT cushions. Furthermore, these mapping studies uncover nodules in the pharyngeal arches, and identify Twist1(-/-) neural crest cell defects within the dorsal neural tube, which exhibits an expanded domain of Wnt1-Cre-lineage marked cells. Together, these data support a model where Twist1 is required both for proper cNCC delamination, and for emigration from the dorsal neural tube and along cNCC migration pathways. Within the Twist1(-/-) neural crest cell populations that do emigrate to the OFT, a Hand-expressing subpopulation displays defective maturation, tracking, and, presumably, cell-cell adhesion, further compromising cNCC morphogenesis.


Assuntos
Coração/embriologia , Morfogênese , Crista Neural/embriologia , Proteínas Nucleares/deficiência , Proteína 1 Relacionada a Twist/deficiência , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Região Branquial/anormalidades , Região Branquial/patologia , Contagem de Células , Morte Celular , Linhagem da Célula , Movimento Celular , Proliferação de Células , Embrião de Mamíferos/anormalidades , Embrião de Mamíferos/patologia , Regulação da Expressão Gênica no Desenvolvimento , Integrases/metabolismo , Mesoderma/anormalidades , Mesoderma/patologia , Camundongos , Músculo Liso/patologia , Mutação/genética , Crista Neural/anormalidades , Tubo Neural/anormalidades , Tubo Neural/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada a Twist/genética , Proteína 1 Relacionada a Twist/metabolismo , Proteínas Wnt/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA