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1.
J Appl Oral Sci ; 27: e20180649, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31596367

RESUMO

OBJECTIVE: Cleft palate (CP) is a congenital birth defect caused by the failure of palatal fusion. Little is known about the potential role of DNA methylation in the pathogenesis of CP. This study aimed to explore the potential role of DNA methylation in the mechanism of CP. METHODOLOGY: We established an all-trans retinoic acid (ATRA)-induced CP model in C57BL/6J mice and used methylation-dependent restriction enzymes (MethylRAD, FspEI) combined with high-throughput sequencing (HiSeq X Ten) to compare genome-wide DNA methylation profiles of embryonic mouse palatal tissues, between embryos from ATRA-treated vs. untreated mice, at embryonic gestation day 14.5 (E14.5) (n=3 per group). To confirm differentially methylated levels of susceptible genes, real-time quantitative PCR (qPCR) was used to correlate expression of differentially methylated genes related to CP. RESULTS: We identified 196 differentially methylated genes, including 17,298 differentially methylated CCGG sites between ATRA-treated vs. untreated embryonic mouse palatal tissues (P<0.05, log2FC>1). The CP-related genes Fgf16 (P=0.008, log2FC=1.13) and Tbx22 (P=0.011, log2FC=1.64,) were hypermethylated. Analysis of Fgf16 and Tbx22, using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), identified 3 GO terms and 1 KEGG pathway functionally related to palatal fusion. The qPCR showed that changes in expression level negatively correlated with methylation levels. CONCLUSIONS: Taken together, these results suggest that hypermethylation of Fgf16 and Tbx22 is associated with decreased gene expression, which might be responsible for developmental failure of palatal fusion, eventually resulting in the formation of CP.


Assuntos
Fissura Palatina/genética , Metilação de DNA , Fatores de Crescimento de Fibroblastos/genética , Expressão Gênica , Proteínas com Domínio T/genética , Animais , Fissura Palatina/embriologia , Fissura Palatina/patologia , Feminino , Fatores de Crescimento de Fibroblastos/análise , Masculino , Camundongos Endogâmicos C57BL , Domínios e Motivos de Interação entre Proteínas , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Análise de Sequência de DNA , Proteínas com Domínio T/análise
3.
Medicine (Baltimore) ; 98(42): e17492, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626103

RESUMO

Fetal pulmonary atresia with intact ventricular septum (PA/IVS) is a rare congenital heart disease. The present study aimed to classify PA/IVS and determine the relationship between prenatal echocardiographic characteristics and postnatal biventricular or univentricular repair strategies.A total of 51 fetuses with PA/IVS were examined from 2012 to 2019. Data on prenatal echocardiography, associated anomaly, karyotype, and outcome were collected. Two-dimensional measurements included tricuspid valve (TV) z-score, mitral valve (MV) z-score, TV/MV ratio, and ratio of right to left ventricle (RV/LV) length, whereas color Doppler measurements included degree of tricuspid regurgitation (TR), ventriculo-coronary artery communication (VCAC), tricuspid inflow duration (TID), cardiac cycle duration (CCD), middle cerebral artery pulsatility index (MCA PI), and umbilical artery pulsatility index (UA PI). Diagnostic classification was based on the development of RV and the presence or absence of VCAC. Postnatal evaluation was divided according biventricular or univentricular repair.Of the 51 fetuses with PA/IVS, 20 were type I, 17 were type II, and 14 were type III. Only one fetus exhibited right aortic arch. The karyotype of all the fetuses was normal. Of the 28 patients who underwent postnatal surgery, 13 (46%) underwent biventricular repair and 15 (54%) underwent univentricular repair. TV z-score was significantly higher for the biventricular repair group compared with univentricular repair group (-1.20 ±â€Š0.98 vs -4.33 ±â€Š0.80, P = .000). TV/MV, RV/LV length, and TID/CCD were significantly higher for the biventricular repair group than the univentricular repair group (0.81 ±â€Š0.14 vs 0.54 ±â€Š0.09, 0.71 ±â€Š0.11 vs 0.49 ±â€Š0.09, 39.20 ±â€Š3.84 vs 29.16 ±â€Š4.58, P = .000). Moderate or severe TR and VCAC were significantly different between the 2 groups (P = .000). Gestational age, MCA PI, and UA PI did not differ between the 2 groups (P = .72, P = .36, P = .06). The cutoff values for the biventricular repair characteristic curves were TV z-score >-3.28, TV/MV ratio >0.71, RV/LV length >0.62, and TID/CCD >33.95%. The sensitivities of the TV z-score, TV/MV, RV/LV length, and TID/CCD were 100%, 77%, 85%, and 92%, respectively. The specificities of the TV z-score, TV/MV, RV/LV length, and TID/CCD were 94%, 100%, 100%, and 94%, respectively.Fetal echocardiography was able to classify PA/IVS according to variable degree of RV and VCAC. In fetal PA/IVS, TV z-score >-3.28, TV/MV >0.71, RV/LV length >0.62, TID/CCD >33.95%, moderate and severe TR, and the absence of VCAC were associated with postnatal biventricular repair strategy. These findings may have implications for prenatal counseling and prediction of fetal outcome.


Assuntos
Ecocardiografia/estatística & dados numéricos , Coração Fetal/diagnóstico por imagem , Cardiopatias Congênitas/classificação , Cardiopatias Congênitas/diagnóstico por imagem , Atresia Pulmonar/classificação , Atresia Pulmonar/diagnóstico por imagem , Ultrassonografia Pré-Natal/estatística & dados numéricos , Adulto , Ecocardiografia/métodos , Feminino , Idade Gestacional , Cardiopatias Congênitas/embriologia , Humanos , Valor Preditivo dos Testes , Gravidez , Prognóstico , Atresia Pulmonar/embriologia , Valores de Referência , Sensibilidade e Especificidade , Ultrassonografia Pré-Natal/métodos , Adulto Jovem
5.
Rinsho Ketsueki ; 60(9): 1283-1291, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597854

RESUMO

It is well known that platelets play a crucial role in hemostasis, but it has recently been revealed that platelets are also necessary for organ development. The platelet activation receptor CLEC-2 activates platelets by binding to the membrane protein, podoplanin, on the surface of lymphatic endothelial cells. This results in the release of TGF-ß family from activated platelets to facilitate blood/lymphatic vessel separation. TGF-ß also acts on lung mesothelial cells, which leads to their differentiation into alveolar duct myofibroblasts (adMYFs) and their migration into the inside of the lung. adMYFs generate elastin, which gives elasticity to the lung. Therefore, mice deficient in either CLEC-2 or podoplanin exhibit blood/lymphatic vessel misconnection and die just after birth due to respiratory failure. It had been previously surmised that biologically active substances from cells act on neighboring cells, leading to organ development, and the role of blood cells in organ development had not been elucidated. However, it has recently been demonstrated that blood platelets contain biological active substances in their granules, which are released when and where necessary by specific interactions between platelet receptors and their ligands. Now platelets are recognized as a "biological package" that actively facilitates organ development.


Assuntos
Plaquetas/citologia , Pulmão/embriologia , Animais , Células Endoteliais , Hemostasia , Camundongos
6.
Results Probl Cell Differ ; 68: 3-20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598850

RESUMO

This chapter reflects on and makes explicit the distinctiveness of reasoning practices associated with model organisms in the context of evolutionary developmental research. Model organisms in evo-devo instantiate a unique synthesis of model systems strategies from developmental biology and comparative strategies from evolutionary biology that negotiate a tension between developmental conservation and evolutionary change to address scientific questions about the evolution of development and the developmental basis of evolutionary change. We review different categories of model systems that have been advanced to understand practices found in the life sciences in order to comprehend how evo-devo model organisms instantiate this synthesis in the context of three examples: the starlet sea anemone and the evolution of bilateral symmetry, leeches and the origins of segmentation in bilaterians, and the corn snake to understand major evolutionary change in axial and appendicular morphology.


Assuntos
Evolução Biológica , Biologia do Desenvolvimento , Modelos Animais , Animais , Sanguessugas/embriologia , Anêmonas-do-Mar/embriologia , Serpentes/embriologia
7.
Results Probl Cell Differ ; 68: 63-105, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598853

RESUMO

The urochordate Oikopleura dioica is emerging as a nonclassical animal model in the field of evolutionary developmental biology (a.k.a. evo-devo) especially attractive for investigating the impact of gene loss on the evolution of mechanisms of development. This is because this organism fulfills the requirements of an animal model (i.e., has a simple and accessible morphology, a short generation time and life span, and affordable culture in the laboratory and amenable experimental manipulation), but also because O. dioica occupies a key phylogenetic position to understand the diversification and origin of our own phylum, the chordates. During its evolution, O. dioica genome has suffered a drastic process of compaction, becoming the smallest known chordate genome, a process that has been accompanied by exacerbating amount of gene losses. Interestingly, however, despite the extensive gene losses, including entire regulatory pathways essential for the embryonic development of other chordates, O. dioica retains the typical chordate body plan. This unexpected situation led to the formulation of the so-called inverse paradox of evo-devo, that is, when a genetic diversity is able to maintain a phenotypic unity. This chapter reviews the biological features of O. dioica as a model animal, along with the current data on the evolution of its genes and genome. We pay special attention to the numerous examples of gene losses that have taken place during the evolution of this unique animal model, which is helping us to understand to which the limits of evo-devo can be pushed off.


Assuntos
Biologia do Desenvolvimento , Evolução Molecular , Deleção de Genes , Modelos Animais , Urocordados/embriologia , Urocordados/genética , Animais , Filogenia
8.
Results Probl Cell Differ ; 68: 127-154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598855

RESUMO

Cells are arranged into species-specific patterns during early embryogenesis. Such cell division patterns are important since they often reflect the distribution of localized cortical factors from eggs/fertilized eggs to specific cells as well as the emergence of organismal form. However, it has proven difficult to reveal the mechanisms that underlie the emergence of cell positioning patterns that underlie embryonic shape, likely because a systems-level approach is required that integrates cell biological, genetic, developmental, and mechanical parameters. The choice of organism to address such questions is also important. Because ascidians display the most extreme form of invariant cleavage pattern among the metazoans, we have been analyzing the cell biological mechanisms that underpin three aspects of cell division (unequal cell division (UCD), oriented cell division (OCD), and asynchronous cell cycles) which affect the overall shape of the blastula-stage ascidian embryo composed of 64 cells. In ascidians, UCD creates two small cells at the 16-cell stage that in turn undergo two further successive rounds of UCD. Starting at the 16-cell stage, the cell cycle becomes asynchronous, whereby the vegetal half divides before the animal half, thus creating 24-, 32-, 44-, and then 64-cell stages. Perturbing either UCD or the alternate cell division rhythm perturbs cell position. We propose that dynamic cell shape changes propagate throughout the embryo via cell-cell contacts to create the ascidian-specific invariant cleavage pattern.


Assuntos
Padronização Corporal , Divisão Celular , Embrião não Mamífero/citologia , Embrião não Mamífero/embriologia , Urocordados/citologia , Urocordados/embriologia , Animais , Fertilização
9.
Results Probl Cell Differ ; 68: 183-216, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598857

RESUMO

All extant species are an outcome of nature's "experiments" during evolution, and hence multiple species need to be studied and compared to gain a thorough understanding of evolutionary processes. The field of evolutionary developmental biology (evo-devo) aspires to expand the number of species studied, because most functional genetic studies in animals have been limited to a small number of "traditional" model organisms, many of which belong to the same phylum (Chordata). The phylum Arthropoda, and particularly its component class Insecta, possesses many important characteristics that are considered favorable and attractive for evo-devo research, including an astonishing diversity of extant species and a wide disparity in body plans. The development of the most thoroughly investigated insect genetic model system to date, the fruit fly Drosophila melanogaster (a holometabolous insect), appears highly derived with respect to other insects and indeed with respect to most arthropods. In comparison, crickets (a basally branching hemimetabolous insect lineage compared to the Holometabola) are thought to embody many developmental features that make them more representative of insects. Here we focus on crickets as emerging models to study problems in a wide range of biological areas and summarize the currently available molecular, genomic, forward and reverse genetic, imaging and computational tool kit that has been established or adapted for cricket research. With an emphasis on the cricket species Gryllus bimaculatus, we highlight recent efforts made by the scientific community in establishing this species as a laboratory model for cellular biology and developmental genetics. This broad toolkit has the potential to accelerate many traditional areas of cricket research, including studies of adaptation, evolution, neuroethology, physiology, endocrinology, regeneration, and reproductive behavior. It may also help to establish newer areas, for example, the use of crickets as animal infection model systems and human food sources.


Assuntos
Gryllidae/genética , Gryllidae/fisiologia , Modelos Animais , Animais , Drosophila melanogaster , Abastecimento de Alimentos , Gryllidae/embriologia , Gryllidae/microbiologia
10.
Results Probl Cell Differ ; 68: 321-353, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598863

RESUMO

When shifting research focus from model to non-model species, many differences in the working approach should be taken into account and usually methodological modifications are required because of the lack of genetics/genomics and developmental information for the vast majority of organisms. This lack of data accounts for the largely incomplete understanding of how the two components-genes and developmental programs-are intermingled in the process of evolution. A deeper level of knowledge was reached for a few model animals, making it possible to understand some of the processes that guide developmental changes during evolutionary time. However, it is often difficult to transfer the obtained information to other, even closely related, animals. In this chapter, we present and discuss some examples, such as the choice of molecular markers to be used to characterize differentiation and developmental processes. The chosen examples pertain to the study of germline in molluscs, reptiles, and other non-model animals.


Assuntos
Biomarcadores/metabolismo , Diferenciação Celular , Células Germinativas/citologia , Células Germinativas/metabolismo , Moluscos/citologia , Répteis , Animais , Biomarcadores/análise , Répteis/embriologia
11.
Results Probl Cell Differ ; 68: 379-418, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598865

RESUMO

The developmental adaptations of the marsupial frogs Gastrotheca riobambae and Flectonotus pygmaeus (Hemiphractidae) are described and compared with frogs belonging to seven additional families. Incubation of embryos by the mother in marsupial frogs is associated with changes in the anatomy and physiology of the female, modifications of oogenesis, and extraordinary changes in embryonic development. The comparison of early development reveals that gene expression is highly conserved. However, the timing of gene expression varies between frog species. There are two modes of gastrulation according to the onset of convergent extension. In gastrulation mode 1, convergent extension is an intrinsic mechanism of gastrulation. This gastrulation mode occurs in frogs with aquatic reproduction, such as Xenopus laevis. In gastrulation mode 2, convergent extension occurs after the completion of gastrulation movements. Gastrulation mode 2 occurs in frogs with terrestrial reproduction, such as the marsupial frog, G. riobambae. The two modes of frog gastrulation resemble the two transitions toward meroblastic cleavage of ray-finned fishes (Actinopterygii). The comparison indicates that a major event in the evolution of frog terrestrial development is the separation of convergent extension from gastrulation.


Assuntos
Anuros/embriologia , Embrião não Mamífero/embriologia , Desenvolvimento Embrionário , Animais , Gástrula/embriologia , Xenopus laevis/embriologia
12.
Results Probl Cell Differ ; 68: 455-475, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598867

RESUMO

Nutritional modes operating during embryonic/larval development of viviparous species range from "pure" lecitothrophy in which embryos rely solely on reserve materials (yolk spheres, lipid droplets, and glycogen particles) accumulated in the egg cytoplasm to matrotrophy in which embryos are continuously supplied with nutrients from a parental organism. Interestingly, a wide spectrum of diverse "mixed" modes employed in the embryo nourishment have also been described among viviparous species. Here, we summarize results of histochemical, ultrastructural, and biochemical analyses of reproductive systems as well as developing embryos of two closely related viviparous species of earwigs (Dermaptera), Hemimerus talpoides and Arixenia esau. These analyses clearly indicate that morphological as well as physiological modifications (adaptations) supporting viviparity and matrotrophy in Hemimerus and Arixenia, with the exception of a complex biphasic respiration, are markedly different. Most importantly, Hemimerus embryos complete their development inside terminal (largest) ovarian follicles, whereas Arixenia embryos, after initial developmental stages, are transferred to highly modified lateral oviducts, that is the uterus, where they develop until the release (birth) of larvae. The obtained results strongly suggest that viviparity in hemimerids and arixeniids had evolved independently and might therefore serve as an example of evolutionary parallelism as well as remarkable functional plasticity of insect reproduction and embryonic development.


Assuntos
Evolução Biológica , Desenvolvimento Embrionário , Neópteros/embriologia , Neópteros/fisiologia , Folículo Ovariano/fisiologia , Oviductos/fisiologia , Reprodução/fisiologia , Viviparidade não Mamífera/fisiologia , Animais , Feminino , Larva , Neópteros/anatomia & histologia
13.
J Environ Sci (China) ; 85: 1-8, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31471016

RESUMO

Metalaxyl is an anilide pesticide that is widely used to control plant diseases caused by Peronosporales species. In order to study the toxic effects, zebrafish embryos were exposed to metalaxyl at nominal concentrations of 5, 50 and 500 ng/L for 72 hr, and the cardiac development and functioning of larvae were observed. The results showed that metalaxyl exposure resulted in increased rates of pericardial edema, heart hemorrhage and cardiac malformation. The distance between the sinus venosus and bulbus arteriosus, stroke volume, cardiac output and heart rate were significantly increased in larvae exposed to 50 and 500 ng/L metalaxyl compared to solvent control larvae. Significant upregulation in the transcription of tbx5, gata4 and myh6 was observed in the 50 and 500 ng/L treatments, and that of nkx2.5 and myl7 was observed in the 5, 50 and 500 ng/L groups. These disturbances may be related to cardiac developmental and functional defects in the larvae. The activity of Na+/K+-ATPase and Ca2+-ATPase was significantly increased in zebrafish embryos exposed to 500 ng/L metalaxyl, and the mRNA levels of genes related to ATPase (atp2a11, atp1b2b, and atp1a3b) (in the 50 and 500 ng/L groups) and calcium channels (cacna1ab) (in the 500 ng/L group) were significantly downregulated; these changes might be associated with heart arrhythmia and functional failure.


Assuntos
Alanina/análogos & derivados , Coração/crescimento & desenvolvimento , Poluentes Químicos da Água/toxicidade , Alanina/toxicidade , Animais , Embrião não Mamífero , Coração/efeitos dos fármacos , Peixe-Zebra/embriologia
15.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 33(9): 1174-1180, 2019 Sep 15.
Artigo em Chinês | MEDLINE | ID: mdl-31512462

RESUMO

Objective: To investigate the correlation between down-regulation of miR-381-3p and inhibition of osteogenic differentiation of mouse embryonic palatal mesenchymal (MEPM) cells in 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-induced cleft palate of fetal mice. Methods: Thirty-two pregnant mice were randomly divided into TCDD group and control group, 16 in each group. On embryonic day 10.5 (E10.5), the pregnant mice in TCDD group were orally administrated with TCDD at dosage of 28 µg/kg, while the pregnant mice in control group received equivalent corn oil. The pregnant mice in each group were sacrificed on E13.5 and E14.5, fetal palates were collected for analysis. The expression of miR-381-3p was detected by real-time fluorescent quantitative PCR and the protein expressions of runt- related transcription factor 2 (RUNX2) and osteopontin (OPN) were detected by Western blot. MEPM cells were extracted from fetal palates on E14.5 in control group and passaged. The 3rd passage cells were cultured with TCDD at dosage of 10 nmol/L for 0, 0.5, 1, 2, and 3 days. The expression of miR-381-3p was detected after 0, 0.5, 1, 2, and 3 days and the protein expressions of RUNX2 and OPN were detected after 0, 1, 2, and 3 days. Then, the 3rd passage cells were divided into 4 groups. The MEPM cells were transfected with miR-381-3p inhibitor (inhibitor group), NC inhibitor (NC inhibitor group) and miR-381-3p mimics (mimics group), NC mimics (NC mimics group) for 48 hours, respectively. And the expressions of miR-381-3p and the protein expressions of RUNX2 and OPN were detected. Results: On E13.5 and E14.5, 96 fetal mice in control group and 92 in TCDD group were obtained. The bilateral palates contacted in control group on E14.5, and a gap between the bilateral palates existed in TCDD group. On E13.5 and E14.5, the relative expressions of miR-381-3p and RUNX2 and OPN proteins were significant lower in TCDD group than in control group ( P<0.05). The relative expression of miR-381-3p at 0.5 and 1 day after TCDD treatment of MEPM cells were significantly lower than that at 0 day ( P<0.05); then, the relative expressions at 2 and 3 days significantly increased, showing no significant difference when compared with that at 0 day ( P>0.05). The relative expressions of RUNX2 and OPN proteins at 1, 2, and 3 days were significantly lower than that at 0 day ( P<0.05). The relative expressions of miR-381-3p and RUNX2 and OPN proteins significantly lower in inhibitor group than in NC inhibitor group ( P<0.05) and higher in mimics group than in NC mimics group ( P<0.05). Conclusion: Down-regulation of miR-381-3p expression may be associated with inhibition of osteogenic differentiation of MEPM cells in TCDD-induced cleft palate of fetal mice.


Assuntos
Fissura Palatina , Regulação para Baixo , MicroRNAs , Dibenzodioxinas Policloradas , Animais , Fissura Palatina/induzido quimicamente , Fissura Palatina/embriologia , Fissura Palatina/genética , Fissura Palatina/fisiopatologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Osteogênese/genética , Palato/fisiopatologia , Gravidez
16.
Adv Gerontol ; 32(3): 357-363, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31512421

RESUMO

The aim of this work was to examine the content of Piezo1 in fibroblasts and blood vessels of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and defining of a role of Piezo1 in age-dependent changes in the number of fibroblasts and blood vessels in the dermis. Piezo1, proliferating cells nuclear antigen (PCNA), endothelial cells marker CD31 were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for Piezo1 in the dermis is decreased from 20 weeks of pregnancy to 40 years old. Percent of Piezo1 positive fibroblasts in dermis is increased sufficiently since 41 years old until 60-85 years old group. The content of Piezo1 in blood vessels in the human dermis is decreased sufficiently from 20 weeks of pregnancy until 40 years old. Age-related changes in the content of Piezo1 in fibroblasts and blood vessels is not associated with an age-related decrease in total number and percent of PCNA positive fibroblasts, the number of blood vessels in the dermis.


Assuntos
Vasos Sanguíneos , Derme , Fibroblastos , Canais Iônicos , Envelhecimento da Pele , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasos Sanguíneos/fisiologia , Criança , Pré-Escolar , Derme/irrigação sanguínea , Derme/citologia , Derme/embriologia , Derme/crescimento & desenvolvimento , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Lactente , Canais Iônicos/metabolismo , Masculino , Pessoa de Meia-Idade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Gravidez , Antígeno Nuclear de Célula em Proliferação/metabolismo , Envelhecimento da Pele/fisiologia
17.
Chemosphere ; 235: 1050-1058, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31561294

RESUMO

Lead (Pb) is one of the most toxic heavy metals and has aroused widespread concern as it can cause severe impairments in the developing nervous system. Autophagy has been proposed as an injury factor in Pb-induced neurotoxicity. In this study, we used zebrafish embryo as a model, measured the general toxic effects of Pb, and investigated the effect of Pb exposure on autophagy, and its role in Pb-induced developmental neurotoxicity. Zebrafish embryos were exposed to Pb at concentrations of 0, 0.1, 1 or 10 µM until 4 days post-fertilization. Our data showed that exposure to 10 µM Pb significantly reduced survival rates and impaired locomotor activity. Uptake of Pb was enhanced as the concentration and duration of exposure increased. Inhibition of lysosomal degradation with bafilomycin A1 treatment abolished the suppression of Lc3-II protein expression by Pb. Furthermore, autophagosome formation was inhibited by Pb in the brain. In addition, mRNA expression of beclin1, one of the critical genes in autophagy, were decreased in Pb exposure groups at 72 h post-fertilization. Whole-mount in situ hybridization assay showed that beclin1 gene expression in the brain was reduced by Pb. Rapamycin, an autophagy inducer, partly resolved developmental neurotoxicity induced by Pb exposure. Our results suggest that autophagy plays a protective role in the developmental neurotoxicity of Pb in zebrafish embryos and larvae.


Assuntos
Autofagia/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo/prevenção & controle , Chumbo/toxicidade , Peixe-Zebra/embriologia , Animais , Expressão Gênica , Larva/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo
18.
Nat Neurosci ; 22(10): 1624-1634, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31551593

RESUMO

Hundreds of genes are implicated in autism spectrum disorder (ASD), but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here we analyzed leukocyte transcriptomics from 1- to 4-year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes highly expressed genes during fetal brain development. This network is dysregulated in human induced pluripotent stem cell-derived neuron models of ASD. High-confidence ASD risk genes emerge as upstream regulators of the network, and many risk genes may impact the network by modulating RAS-ERK, PI3K-AKT and WNT-ß-catenin signaling pathways. We found that the degree of dysregulation in this network correlated with the severity of ASD symptoms in the toddlers. These results demonstrate how the heterogeneous genetics of ASD may dysregulate a core network to influence brain development at prenatal and very early postnatal ages and, thereby, the severity of later ASD symptoms.


Assuntos
Transtorno do Espectro Autista/genética , Redes Reguladoras de Genes/genética , Transtorno do Espectro Autista/patologia , Encéfalo/embriologia , Encéfalo/patologia , Pré-Escolar , Desenvolvimento Fetal/genética , Humanos , Lactente , Leucócitos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Mutação/genética , Células-Tronco Neurais , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/genética , Via de Sinalização Wnt/genética , beta Catenina/genética
20.
Gene ; 718: 144049, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31430520

RESUMO

The role of epigenetics in development has garnered attention in recent years due to their ability to modulate the embryonic developmental gene expression in response to the environmental cues. The epigenetic mechanisms - DNA methylation, histone modification, and non-coding RNAs have a unique impact on vertebrate development. Zebrafish, a model vertebrate organism is being used widely in developmental studies due to their high fecundability and rapid organogenesis. With increased studies on various aspects of epigenetics in development, this review gives a glimpse of the major epigenetic modifications and their role in zebrafish development. In this review, the basic mechanism behind each modification followed by their status in zebrafish has been reviewed. Further, recent advancements in the epigenetic aspect of zebrafish development have been discussed.


Assuntos
Metilação de DNA/fisiologia , Embrião não Mamífero/embriologia , Desenvolvimento Embrionário/fisiologia , Epigênese Genética/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Peixe-Zebra/embriologia , Animais , Histonas/genética , Histonas/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Peixe-Zebra/genética
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