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1.
Adv Exp Med Biol ; 1236: 65-85, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304069

RESUMO

The pancreas is a glandular organ responsible for diverse homeostatic functions, including hormone production from the endocrine islet cells to regulate blood sugar levels and enzyme secretion from the exocrine acinar cells to facilitate food digestion. These pancreatic functions are essential for life; therefore, preserving pancreatic function is of utmost importance. Pancreas dysfunction can arise either from developmental disorders or adult onset disease, both of which are caused by defects in shared molecular pathways. In this chapter, we discuss what is known about the molecular mechanisms controlling pancreas development, how disruption of these mechanisms can lead to developmental defects and disease, and how essential pancreas functions can be modeled using human pluripotent stem cells. At the core of understanding of these molecular processes are animal model studies that continue to be essential for elucidating the mechanisms underlying human pancreatic functions and diseases.


Assuntos
Modelos Animais , Organogênese , Pâncreas/embriologia , Pâncreas/patologia , Células Acinares/metabolismo , Células Acinares/patologia , Animais , Humanos , Pâncreas/citologia , Pâncreas Exócrino/citologia , Pâncreas Exócrino/embriologia , Pâncreas Exócrino/patologia , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/patologia
2.
Nat Cell Biol ; 22(4): 487-497, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231307

RESUMO

During mouse embryonic development, pluripotent cells rapidly divide and diversify, yet the regulatory programs that define the cell repertoire for each organ remain ill-defined. To delineate comprehensive chromatin landscapes during early organogenesis, we mapped chromatin accessibility in 19,453 single nuclei from mouse embryos at 8.25 days post-fertilization. Identification of cell-type-specific regions of open chromatin pinpointed two TAL1-bound endothelial enhancers, which we validated using transgenic mouse assays. Integrated gene expression and transcription factor motif enrichment analyses highlighted cell-type-specific transcriptional regulators. Subsequent in vivo experiments in zebrafish revealed a role for the ETS factor FEV in endothelial identity downstream of ETV2 (Etsrp in zebrafish). Concerted in vivo validation experiments in mouse and zebrafish thus illustrate how single-cell open chromatin maps, representative of a mammalian embryo, provide access to the regulatory blueprint for mammalian organogenesis.


Assuntos
Cromatina/química , Células Endoteliais/metabolismo , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica no Desenvolvimento , Organogênese/genética , Proteína 1 de Leucemia Linfocítica Aguda de Células T/genética , Animais , Linhagem da Célula/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Cromatina/metabolismo , Embrião de Mamíferos , Embrião não Mamífero , Desenvolvimento Embrionário , Células Endoteliais/citologia , Perfilação da Expressão Gênica , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos , Ligação Proteica , Análise de Célula Única , Proteína 1 de Leucemia Linfocítica Aguda de Células T/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Genética , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
3.
Gene ; 731: 144334, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31935508

RESUMO

SOX9 plays a crucial, extensive and conservative role in the process of somatic tissue development and adult regeneration through the positive self-regulation mediated by SOM across all vertebrates. In this study, we have cloned SOX9 from the kidney of hatchling Alligator sinensis. The full-length of SOX9 cDNA is 3878 bp with an open reading frame encoding 494 amino acids. Amino acid alignment analyses indicated that the SOX9 exhibit highly conserved functional domains. Using the droplet digital PCR, the mRNA abundances of SOX9 during nephrogenesis in A. sinensis showed prominent changes in the embryonic development, suggesting that SOX9 might combines a vital role in the regulation of complex renal development. Interestingly, we detected the nucleocytoplasmic shuttling of SOX9 protein using immunofluorescence, implying that nucleocytoplasmic shuttling is critical to the regulation of SOX9 in the renal embryonic development. Collectively, these data provide an important foundation for further studies on renal developmental biology and molecular biology of non-mammalian SOX9. Furthermore, it provides new insights into the phenomenon of SOX9 nucleocytoplasmic shuttling in Alligator sinensis, which is probably of great significance to the development of kidney metanephros embryo.


Assuntos
Jacarés e Crocodilos , Rim/embriologia , Rim/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Transporte Ativo do Núcleo Celular , Jacarés e Crocodilos/embriologia , Jacarés e Crocodilos/genética , Jacarés e Crocodilos/metabolismo , Animais , Núcleo Celular/metabolismo , Clonagem Molecular , Regulação da Expressão Gênica no Desenvolvimento , Organogênese/genética , Transporte de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
4.
Life Sci ; 241: 117166, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31843527

RESUMO

AIMS: Congenital diaphragmatic hernia (CDH) is a lethal birth defect characterized by congenital lung malformation, and the severity of pulmonary hypoplasia directly affects the prognosis of infants with CDH. Using a nitrofen-induced CDH rat model, we previously reported that Foxa2 expression was downregulated in CDH lungs by proteomics analysis. Here, we investigate the role of miR-130a-5p/Foxa2 axis in lung development of the nitrofen-induced CDH and evaluate its potential role in vivo prenatal therapy. MAIN METHODS: Nitrofen was orally administrated on embryonic day (E) 8.5 to establish a rat CDH model, and fetal lungs were collected on E13.5, E15.5, E17.5, E19.5 and E21.5. The binding sites of miR-130a-5p on Foxa2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. The expression levels of miR-130a-5p and Foxa2 were detected using qRT-PCR, ISH, IHC and western blotting. The role of miR-130a-5p/Foxa2 axis in CDH-associated lung development was investigated in ex vivo lung explants. KEY FINDINGS: We found that Foxa2 was downregulated in CDH lung tissues, and Foxa2 upregulating improved CDH branching morphogenesis in ex vivo lung explants. Meanwhile, we also showed that miR-130a-5p was significantly upregulated in CDH lungs and thus inversely correlated with Foxa2. Increasing miR-130a-5p abundance with mimics decreases Foxa2-driven Shh/Gli1 signaling and inhibits branching morphogenesis in ex vivo lung explants. SIGNIFICANCE: This study was the first to show that the miR-130a-5p/Foxa2 axis played a crucial role in CDH-associated pulmonary hypoplasia. These findings may provide relevant insights into the prenatal diagnosis and prenatal therapy of CDH.


Assuntos
Desenvolvimento Fetal/genética , Regulação da Expressão Gênica no Desenvolvimento , Fator 3-beta Nuclear de Hepatócito/metabolismo , Hérnias Diafragmáticas Congênitas/patologia , Pulmão/citologia , MicroRNAs/genética , Organogênese , Animais , Proliferação de Células , Células Cultivadas , Feminino , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Fator 3-beta Nuclear de Hepatócito/genética , Herbicidas/toxicidade , Hérnias Diafragmáticas Congênitas/induzido quimicamente , Hérnias Diafragmáticas Congênitas/metabolismo , Pulmão/fisiologia , Masculino , Éteres Fenílicos/toxicidade , Gravidez , Ratos , Ratos Sprague-Dawley , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
5.
Int J Mol Sci ; 21(1)2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31861793

RESUMO

Hedgehog (Hh) signaling is an essential growth factor signaling pathway especially in the regulation of epithelial-mesenchymal interactions (EMI) during the development of the urogenital organs such as the bladder and the external genitalia (EXG). The Hh ligands are often expressed in the epithelia, affecting the surrounding mesenchyme, and thus constituting a form of paracrine signaling. The development of the urogenital organ, therefore, provides an intriguing opportunity to study EMI and its relationship with other pathways, such as hormonal signaling. Cellular interactions of prostate cancer (PCa) with its neighboring tissue is also noteworthy. The local microenvironment, including the bone metastatic site, can release cellular signals which can affect the malignant tumors, and vice versa. Thus, it is necessary to compare possible similarities and divergences in Hh signaling functions and its interaction with other local growth factors, such as BMP (bone morphogenetic protein) between organogenesis and tumorigenesis. Additionally, this review will discuss two pertinent research aspects of Hh signaling: (1) the potential signaling crosstalk between Hh and androgen signaling; and (2) the effect of signaling between the epithelia and the mesenchyme on the status of the basement membrane with extracellular matrix structures located on the epithelial-mesenchymal interface.


Assuntos
Transição Epitelial-Mesenquimal , Proteínas Hedgehog/metabolismo , Neoplasias da Próstata/metabolismo , Androgênios/genética , Androgênios/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Comunicação Celular , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Organogênese , Neoplasias da Próstata/genética , Mapas de Interação de Proteínas , Transdução de Sinais , Microambiente Tumoral
6.
Immunity ; 51(5): 788-790, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31747579

RESUMO

In this issue of Immunity, Zeng et al. use single-cell RNA sequencing analyses of rare samples to shed light on the emergence of thymic stromal cell types, the first developing T lymphocytes, and their possible pre-thymic precursors in the early human fetus.


Assuntos
RNA , Linfócitos T , Feto , Humanos , Organogênese , Análise de Sequência de RNA
7.
Nat Med ; 25(11): 1691-1698, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700187

RESUMO

Millions of people worldwide with incurable end-stage lung disease die because of inadequate treatment options and limited availability of donor organs for lung transplantation1. Current bioengineering strategies to regenerate the lung have not been able to replicate its extraordinary cellular diversity and complex three-dimensional arrangement, which are indispensable for life-sustaining gas exchange2,3. Here we report the successful generation of functional lungs in mice through a conditional blastocyst complementation (CBC) approach that vacates a specific niche in chimeric hosts and allows for initiation of organogenesis by donor mouse pluripotent stem cells (PSCs). We show that wild-type donor PSCs rescued lung formation in genetically defective recipient mouse embryos unable to specify (due to Ctnnb1cnull mutation) or expand (due to Fgfr2cnull mutation) early respiratory endodermal progenitors. Rescued neonates survived into adulthood and had lungs functionally indistinguishable from those of wild-type littermates. Efficient chimera formation and lung complementation required newly developed culture conditions that maintained the developmental potential of the donor PSCs and were associated with global DNA hypomethylation and increased H4 histone acetylation. These results pave the way for the development of new strategies for generating lungs in large animals to enable modeling of human lung disease as well as cell-based therapeutic interventions4-6.


Assuntos
Pneumopatias/terapia , Pulmão/crescimento & desenvolvimento , Células-Tronco Pluripotentes/metabolismo , Regeneração/genética , Acilação/genética , Animais , Blastocisto/metabolismo , Diferenciação Celular/genética , Metilação de DNA/genética , Modelos Animais de Doenças , Histonas/genética , Humanos , Pulmão/patologia , Pneumopatias/patologia , Camundongos , Organogênese/genética , Células-Tronco Pluripotentes/transplante , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , beta Catenina/genética
8.
Int J Mol Sci ; 20(19)2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31623299

RESUMO

Pancreatic organogenesis is a multistep process that requires the cooperation of several signaling pathways. In this context, the role of pancreatic mesenchyme is important to define the epithelium development; nevertheless, the precise space-temporal signaling activation still needs to be clarified. This study reports a dissection of the pancreatic embryogenesis, highlighting the molecular network surrounding the epithelium-mesenchyme interaction. To investigate this crosstalk, pancreatic epithelium and surrounding mesenchyme, at embryonic day 10.5, were collected through laser capture microdissection (LCM) and characterized based on their global gene expression. We performed a bioinformatic analysis to hypothesize crosstalk interactions, validating the most promising genes and verifying the precise localization of their expression in the compartments, by RNA in situ hybridization (ISH). Our analyses pointed out also the c-Met gene, a very well-known factor involved in stimulating motility, morphogenesis, and organ regeneration. We also highlighted the potential crosstalk between Versican (Vcan) and Syndecan4 (Sdc4) since these genes are involved in pancreatic tissue repair, strengthening the concept that the same signaling pathways required during pancreatic embryogenesis are also involved in tissue repair. This finding leads to novel strategies for obtaining functional pancreatic stem cells for cell replacement therapies.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Mesoderma/embriologia , Organogênese , Pâncreas/embriologia , Pâncreas/metabolismo , Transdução de Sinais , Animais , Biologia Computacional/métodos , Desenvolvimento Embrionário , Perfilação da Expressão Gênica , Camundongos
9.
Biomed Res ; 40(5): 179-188, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31597903

RESUMO

Single prenatal exposure to valproic acid (VPA) in rodents is a widely used preclinical model of autism spectrum disorder (ASD). Continuous prenatal VPA exposure has been recently proposed as a new ASD model that closely captures the neuropathological features of ASD, including increases in cerebral cortex volume and the number of cortical upper layer neurons. We investigated the influence of prenatal VPA exposure on the behavior of adult offspring of pregnant dams that received intraperitoneal injections of VPA twice on one day during the genesis of cortical upper layer neurons. Mice exposed to VPA at E14 (E14-VPA) showed typical behavior abnormalities including reduced social interaction, hyperactivity, and poor maze learning due to attention deficit/impulsivity relative to healthy controls. Histological analysis revealed that E14-VPA mice had significantly increased neuronal density and impaired neural activity in the prefrontal cortex, but not the somatosensory area, which is likely linked to the observed abnormalities in social behavior. These results suggest that this VPA exposure method is a good model for gaining new insights into the underlying neuropathology of ASD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/embriologia , Exposição Materna/efeitos adversos , Organogênese/efeitos dos fármacos , Comportamento Social , Ácido Valproico/efeitos adversos , Animais , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/embriologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal
10.
Immunity ; 51(5): 930-948.e6, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31604687

RESUMO

Generation of the first T lymphocytes in the human embryo involves the emergence, migration, and thymus seeding of lymphoid progenitors together with concomitant thymus organogenesis, which is the initial step to establish the entire adaptive immune system. However, the cellular and molecular programs regulating this process remain unclear. We constructed a single-cell transcriptional landscape of human early T lymphopoiesis by using cells from multiple hemogenic and hematopoietic sites spanning embryonic and fetal stages. Among heterogenous early thymic progenitors, one subtype shared common features with a subset of lymphoid progenitors in fetal liver that are known as thymus-seeding progenitors. Unbiased bioinformatics analysis identified a distinct type of pre-thymic lymphoid progenitors in the aorta-gonad-mesonephros (AGM) region. In parallel, we investigated thymic epithelial cell development and potential cell-cell interactions during thymus organogenesis. Together, our data provide insights into human early T lymphopoiesis that prospectively direct T lymphocyte regeneration, which might lead to development of clinical applications.


Assuntos
Diferenciação Celular/genética , Linfopoese/genética , Organogênese/genética , Células Precursoras de Linfócitos T/citologia , Células Precursoras de Linfócitos T/metabolismo , Timo/embriologia , Biomarcadores , Diferenciação Celular/imunologia , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunofenotipagem , Linfopoese/imunologia , Detecção de Sinal Psicológico , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timo/imunologia , Timo/metabolismo , Transcriptoma
11.
Life Sci ; 239: 116937, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31629761

RESUMO

Stem cell therapy using bone marrow derived or mesenchymal stem cells has become a popular option for cardiovascular disease treatment, however the administration of embryonic stem cells has been mostly experimental. Remarkably, most of these ongoing clinical trials involve adult patients, but little is known regarding the safety and efficacy of stem cell therapy in newborns and children battling congenital heart diseases. Furthermore, cell delivery methods involve the administration of stem cells without pre-differentiation, and without consideration for the consequent process of cardiac development. Interestingly, in-vitro studies have demonstrated that the differentiation of embryonic stem cells into cardiomyocytes imitates the stages of cardiogenesis. Wnt signaling plays a profound role during the earliest stages of cardiogenesis and cardiac differentiation. In fact inappropriate Wnt signaling is associated with numerous cardiac disorders especially congenital heart disease. Furthermore, cell-extracellular matrix interactions were shown to be critical for stem cell differentiation and adequate cardiogenesis. Since extracellular matrix molecules are fundamental for maintenance and repair during heart disease and congenital heart disease, they may offer a novel approach for therapy. Herein we aim to review the critical role of Wnt signaling, as well as the profound importance of cell extracellular matrix interaction, during cardiogenesis. Both of these processes are crucial for precise stem cell differentiation into cardiomyocytes and developing efficacious regenerative therapy for congenital heart disease.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Cardiopatias/terapia , Via de Sinalização Wnt/fisiologia , Animais , Diferenciação Celular , Células-Tronco Embrionárias/citologia , Humanos , Células-Tronco Mesenquimais/citologia , Miócitos Cardíacos/metabolismo , Organogênese , Transplante de Células-Tronco/métodos , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/metabolismo
12.
Aquat Toxicol ; 216: 105314, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31561137

RESUMO

The endocrine disruptor Bisphenol A (BPA), a widely employed molecule in plastics, has been shown to affect several biological processes in vertebrates, mostly via binding to nuclear receptors. Neurodevelopmental effects of BPA have been documented in vertebrates and linked to neurodevelopmental disorders, probably because some nuclear receptors are present in the vertebrate brain. Similarly, endocrine disruptors have been shown to affect neurodevelopment in marine invertebrates such as ascidians, mollusks or echinoderms, but whether invertebrate nuclear receptors are involved in the mode-of-action is largely unknown. In this study, we assessed the effect of BPA on larval brain development of the ascidian Phallusia mammillata. We found that BPA is toxic to P. mammillata embryos in a dose-dependent manner (EC50: 11.8µM; LC50: 21µM). Furthermore, micromolar doses of BPA impaired differentiation of the ascidian pigmented cells, by inhibiting otolith movement within the sensory vesicle. We further show that this phenotype is specific to other two bisphenols (BPE and BPF) over a bisphenyl (2,2 DPP). Because in vertebrates the estrogen-related receptor gamma (ERRγ) can bind bisphenols with high affinity but not bisphenyls, we tested whether the ascidian ERR participates in the neurodevelopmental phenotype induced by BPA. Interestingly, P. mammillata ERR is expressed in the larval brain, adjacent to the differentiating otolith. Furthermore, antagonists of vertebrate ERRs also inhibited the otolith movement but not pigmentation. Together our observations suggest that BPA may affect ascidian otolith differentiation by altering Pm-ERR activity whereas otolith pigmentation defects might be due to the known inhibitory effect of bisphenols on tyrosinase enzymatic activity.


Assuntos
Compostos Benzidrílicos/toxicidade , Encéfalo/citologia , Encéfalo/embriologia , Diferenciação Celular/efeitos dos fármacos , Organogênese , Fenóis/toxicidade , Pigmentação , Urocordados/citologia , Animais , Compostos Benzidrílicos/química , Movimento Celular/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Larva/efeitos dos fármacos , Larva/metabolismo , Organogênese/efeitos dos fármacos , Membrana dos Otólitos/citologia , Membrana dos Otólitos/efeitos dos fármacos , Fenóis/química , Pigmentação/efeitos dos fármacos , Receptores Estrogênicos/antagonistas & inibidores , Receptores Estrogênicos/metabolismo , Testes de Toxicidade , Urocordados/embriologia , Poluentes Químicos da Água/toxicidade
14.
Nat Commun ; 10(1): 4297, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541101

RESUMO

Tet-mediated DNA demethylation plays an important role in shaping the epigenetic landscape and chromatin accessibility to control gene expression. While several studies demonstrated pivotal roles of Tet in regulating embryonic development, little is known about their functions in heart development. Here we analyze DNA methylation and hydroxymethylation dynamics during early cardiac development in both human and mice. We find that cardiac-specific deletion of Tet2 and Tet3 in mice (Tet2/3-DKO) leads to ventricular non-compaction cardiomyopathy (NCC) with embryonic lethality. Single-cell RNA-seq analyses reveal a reduction in cardiomyocyte numbers and transcriptional reprogramming in cardiac tissues upon Tet2/3 depletion. Impaired DNA demethylation and reduced chromatin accessibility in Tet2/3-DKO mice further compromised Ying-yang1 (YY1) binding to its genomic targets, and perturbed high-order chromatin organization at key genes involved in heart development. Our studies provide evidence of the physiological role of Tet in regulating DNA methylation dynamics and chromatin organization during early heart development.


Assuntos
Cromatina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Desenvolvimento Embrionário/fisiologia , Organogênese/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Fator de Transcrição YY1/metabolismo , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Domínio Catalítico , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Desmetilação do DNA , Metilação de DNA , Proteínas de Ligação a DNA/genética , Desenvolvimento Embrionário/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Coração/embriologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Organogênese/genética , Proteínas Proto-Oncogênicas/genética
15.
Eur. j. anat ; 23(5): 369-376, sept. 2019. ilus, graf, tab
Artigo em Inglês | IBECS | ID: ibc-183867

RESUMO

Hepatic organogenesis is a complex process involving various molecular and cellular determinants. Knowledge of the anatomical and functional structure of the liver and its relationship with other abdominal organs is fundamental from a surgical point of view. Clinical autopsies were performed upon twelve fetal specimens. Photographic footage was reviewed for fetal livers presenting macroscopic abnormalities, and relevant cases were included. A search was conducted employing terms pertaining hepatic malformations’ morphogenetic, anatomical and pathological features. A thorough review was elaborated introducing an updated classification based on autopsy findings and available literature. Twelve fetal specimens underwent clinical autopsies. Gestational age ranged between 18 and 38 weeks (mean 28 weeks). All livers displayed symmetrical lobes. Seven of them presented at least one dysmorphic feature on macroscopic examination. Hepatic malformations can be classified into anomalies due to excessive development, defective development or extrinsic factors. The relevance of the proper identification of liver malformations lies in the broad spectrum of clinical manifestations with different degrees of morbidity associated with them


No disponible


Assuntos
Humanos , Feto/anormalidades , Feto/anatomia & histologia , Fígado/anormalidades , Fígado/anatomia & histologia , Cadáver , Morfogênese , Autopsia/métodos , Fígado/patologia , Organogênese
16.
Int J Mol Sci ; 20(16)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412620

RESUMO

Two mesenchymal zinc transporters, ZIP7 and ZIP13, play critical roles in dermal development. ZIP7 and ZIP13 are the closest among the conserved mammalian zinc transporters. However, whether their functions are complementary remains a controversial issue. In the present study, we found that the expression of ZIP13, but not ZIP7, is elevated by transforming growth factor beta (TGF-ß) treatment, indicating that TGF-ß-mediated ZIP13 amplification is crucial for collagen production during dermal development. Genome-wide gene expression analysis revealed that ~26% of genes are dependent on either ZIP7 or ZIP13, which is greater than the ~17% of genes dependent on both of them. ZIP7 depletion induces endoplasmic reticulum (ER) stress in mesenchymal stem cells, resulting in significant inhibition of fibrogenic differentiation. However, ZIP13 depletion does not induce ER stress. Though both ZIP7 and ZIP13 contain traditional ER signal peptides for their intracellular localization, their distributions are distinct. When ZIP7 and ZIP13 are coexpressed, their localizations are distinct; ZIP7 is located on the ER, but ZIP13 is located on both the ER and Golgi, indicating that only ZIP13 is a zinc gatekeeper on the Golgi. Our data illustrate that the different actions of ZIP7 and ZIP13 are crucial for dermal development.


Assuntos
Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Derme/embriologia , Derme/metabolismo , Organogênese/genética , Zinco/metabolismo , Animais , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Genoma , Estudo de Associação Genômica Ampla , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos
17.
Results Probl Cell Differ ; 67: 323-336, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31435801

RESUMO

The centrosome, a major microtubule organizer, has important functions in regulating the cytoskeleton as well as the position of cellular structures and orientation of cells within tissues. The centrosome serves as the main cytoskeleton-organizing centre in the cell and is the classical site of microtubule nucleation and anchoring. For these reasons, centrosomes play a very important role in morphogenesis, not just in the early stages of cell divisions but also in the later stages of organogenesis. Many organs such as lung, kidney and blood vessels develop from epithelial tubes that branch into complex networks. Cells in the nervous system also form highly branched structures in order to build complex neuronal networks. During branching morphogenesis, cells have to rearrange within tissues though multicellular branching or through subcellular branching, also known as single-cell branching. For highly branched structures to be formed during embryonic development, the cytoskeleton needs to be extensively remodelled. The centrosome has been shown to play an important role during these events.


Assuntos
Centrossomo/fisiologia , Desenvolvimento Embrionário , Morfogênese , Microtúbulos/metabolismo , Organogênese
18.
Immunol Rev ; 291(1): 123-133, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31402498

RESUMO

Ubiquitination is a form of posttranslational protein modification that affects the activity of target proteins by regulating their intracellular degradation, trafficking, localization, and association with other regulators. Recent studies have placed protein ubiquitination as an important regulatory mode to control immune system development, function, and pathogenesis. In this review, we will mainly update the research progress from our laboratory on the roles of the Cbl family of E3 ubiquitin ligases in the development and function of lymphocytes and non-lymphoid cells. In addition, we will highlight our current understanding of the mechanisms used by this family of proteins, especially Cbl and Cbl-b, to co-ordinately regulate the function of various receptors and transcription factors in the context of immune regulation and diseases.


Assuntos
Sistema Imunitário/metabolismo , Organogênese/imunologia , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Homeostase , Humanos , Tolerância Imunológica , Ativação Linfocitária/imunologia , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Ubiquitinação
19.
J Vasc Res ; 56(6): 273-283, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31466069

RESUMO

Cardiovascular diseases such as coronary heart disease, myocardial infarction, and cardiac arrhythmia are the leading causes of morbidity and mortality in developed countries and are steadily increasing in developing countries. Fundamental mechanistic studies at the molecular, cellular, and animal model levels are critical for the diagnosis and treatment of these diseases. Despite being phylogenetically distant from humans, zebrafish share remarkable similarity in the genetics and electrophysiology of the cardiovascular system. In the last 2 decades, the development and deployment of innovative genetic manipulation techniques greatly facilitated the application of zebrafish as an animal model for studying basic biology and diseases. Hemodynamic shear stress is intimately involved in vascular development and homeostasis. The critical mechanosensitive signaling pathways in cardiovascular development and pathophysiology previously studied in mammals have been recapitulated in zebrafish. In this short article, we reviewed recent knowledge about the role of mechanosensitive pathways such as Notch, PKCε/PFKFB3, and Wnt/Ang2 in cardiovas-cular development and homeostasis from studies in the -zebrafish model.


Assuntos
Sistema Cardiovascular/metabolismo , Hemodinâmica , Mecanotransdução Celular , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Sistema Cardiovascular/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Homeostase , Organogênese , Estresse Mecânico , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
20.
Int J Mol Sci ; 20(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31454991

RESUMO

Over the past two decades, studies have demonstrated that several features of T-cell and thymic development are conserved from teleosts to mammals. In particular, works using zebrafish (Danio rerio) and medaka (Oryzias latipes) have shed light on the cellular and molecular mechanisms underlying these biological processes. In particular, the ease of noninvasive in vivo imaging of these species enables direct visualization of all events associated with these processes, which are, in mice, technically very demanding. In this review, we focus on defining the similarities and differences between zebrafish and medaka in T-cell development and thymus organogenesis; and highlight their advantages as two complementary model systems for T-cell immunobiology and modeling of human diseases.


Assuntos
Oryzias/embriologia , Oryzias/imunologia , Linfócitos T/citologia , Linfócitos T/fisiologia , Timo/embriologia , Peixe-Zebra/embriologia , Peixe-Zebra/imunologia , Animais , Biomarcadores , Diferenciação Celular , Testes Genéticos , Humanos , Imagem Molecular , Organogênese , Especificidade da Espécie
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