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1.
Aquat Toxicol ; 219: 105384, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31869577

RESUMO

Tritium (3H), a radioactive isotope of hydrogen, is ubiquitously present in the environment. In a previous study, we highlighted a mis-regulation of genes involved in muscle contraction, eye transparency and response to DNA damages after exposure of zebrafish embryo-larvae from 3 hpf to 96 hpf at 0.4 and 4 mGy/h of tritiated water (HTO). The present study aimed to link this gene mis-regulation to responses observed at higher biological levels. Analyses on spontaneous tail movement, locomotor activity and heart rate were performed. Histological sections of eyes were made to evaluate the impact of HTO on eye transparency and whole embryo immunostainings were realized to assess DNA double strand breaks repair using gamma-H2AX foci. We found a decrease of basal velocity as well as a decrease of response in 96 hpf larvae exposed at 0.4 mGy/h after a tactile stimulus as compared to controls. Histological sections of larvae eyes performed after the exposure to 4 mGy/h did not show obvious differences in lens transparency or retinal development between contaminated and control organisms. Gamma-H2AX foci detection revealed no differences in the number of foci between contaminated organisms and controls, for both dose rates. Overall, results highlighted more detrimental effects of HTO exposure on locomotor behavior in 96 hpf larvae exposed at the lowest dose rate. Those results could be linked to mis-regulation of genes involved in muscle contraction found in a previous study at the same dose rate. It appears that not all effects found at the molecular scale were confirmed using higher biological scales. These results could be due to a delay between gene expression modulation and the onset of physiological disruption or homeostatic mechanisms to deal with tritium effects. However, crossing data from different scales highlighted new pathways to explore, i.e. neurotoxic pathways, for better understanding HTO effects on organisms.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Larva/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Trítio/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Animais , Dano ao DNA , Olho/efeitos dos fármacos , Olho/crescimento & desenvolvimento , Olho/patologia , Larva/genética , Peixe-Zebra/genética
2.
Invest Ophthalmol Vis Sci ; 60(13): 4178-4186, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31596926

RESUMO

Purpose: To examine, in Norwegian adolescents, to what degree emmetropia and low hyperopia were maintained from 16 to 18 years of age, and if this was the case, whether it was associated with continued coordinated ocular growth. Methods: Cycloplegic autorefraction and ocular biometry, including crystalline lens thickness, were measured in 93 Norwegian adolescents (mean age: 16.7 ± 0.3 years; 63.4% females) and repeated after 2 years. Crystalline lens power was determined by ray tracing over a 1-mm pupil, based on the Gullstrand-Emsley model. Serum vitamin D3 concentration was measured at follow-up. Results: Emmetropia and low hyperopia (-0.50 diopters [D] < spherical equivalent refractive error [SER] < +2.00 D) were present in 91.4% at baseline and 89.2% at follow-up. The emmetropes and low hyperopes who maintained their refractive error exhibited continued ocular axial growth (+0.059 ± 0.070 mm) together with a decrease in crystalline lens power (-0.064 ± 0.291 D) and a deepening of the anterior chamber (+0.028 ± 0.040 mm). Thinning of the crystalline lens was found in 24%. Overall, the negative change in SER was larger in those with the most negative SER at baseline (R2 = 0.178, P < 0.001), and was associated with increases in vitreous chamber depth and in crystalline lens power (R2 = 0.752, P < 0.001), when adjusted for sex. There was no difference in vitamin D3 level between those who exhibited negative versus positive changes in refractive error. Conclusions: The results show that emmetropic and low hyperopic eyes were still growing in late adolescence, with refractive errors being maintained through a coordinated decrease in crystalline lens power.


Assuntos
Emetropia/fisiologia , Olho/crescimento & desenvolvimento , Adolescente , Estudos Transversais , Feminino , Humanos , Hiperopia/epidemiologia , Masculino , Noruega/epidemiologia , Prevalência
3.
Exp Eye Res ; 189: 107822, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31585120

RESUMO

Stroboscopic luminance flicker has been found to prevent the increase in eye growth normally associated with form deprivation through the release of retinal dopamine. In this study, we sought to investigate whether dopamine plays a role in the decreased growth observed with 2 Hz sine-wave luminance flicker and increased growth with color flicker. Starting 5-7 days after hatching, chicks were exposed to 2 Hz sinusoidally modulated illumination (Mean: 680 lux) for 4 days and were otherwise in the dark. Chicks were exposed to color-modulated red and green (RG) light, to luminance modulated RGB components (LUM), or to a no-flicker (NF) control. Chicks received daily 10 µL intravitreal injections of apomorphine, spiperone, or saline. Fellow eyes received no injection. Spiperone injections prevented the decrease in eye growth typically seen with LUM flicker, with a relative increase in eye length, but no other significant effects compared with saline controls. Apomorphine injections prevented the increase in eye growth typically seen with RG flicker, with a relative decrease in eye length compared to saline controls. These results indicate a role for the activation of D2-receptor types in the inhibition of eye growth in response to luminance flicker, and a lack of dopamine receptor activation associated with the increase in eye growth with color flicker.


Assuntos
Percepção de Cores/fisiologia , Dopamina/metabolismo , Olho/crescimento & desenvolvimento , Luz , Animais , Animais Recém-Nascidos , Galinhas , Modelos Animais de Doenças , Modelos Animais , Estimulação Luminosa
4.
PLoS Comput Biol ; 15(9): e1007324, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31527870

RESUMO

Reverse engineering of gene regulatory networks (GRNs) is a central task in systems biology. Most of the existing methods for GRN inference rely on gene co-expression analysis or TF-target binding information, where the determination of co-expression is often unreliable merely based on gene expression levels, and the TF-target binding data from high-throughput experiments may be noisy, leading to a high ratio of false links and missed links, especially for large-scale networks. In recent years, the microscopy images recording spatial gene expression have become a new resource in GRN reconstruction, as the spatial and temporal expression patterns contain much abundant gene interaction information. Till now, the spatial expression resources have been largely underexploited, and only a few traditional image processing methods have been employed in the image-based GRN reconstruction. Moreover, co-expression analysis using conventional measurements based on image similarity may be inaccurate, because it is the local-pattern consistency rather than global-image-similarity that determines gene-gene interactions. Here we present GripDL (Gene regulatory interaction prediction via Deep Learning), which incorporates high-confidence TF-gene regulation knowledge from previous studies, and constructs GRNs for Drosophila eye development based on Drosophila embryonic gene expression images. Benefitting from the powerful representation ability of deep neural networks and the supervision information of known interactions, the new method outperforms traditional methods with a large margin and reveals new intriguing knowledge about Drosophila eye development.


Assuntos
Biologia Computacional/métodos , Aprendizado Profundo , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes/genética , Animais , Bases de Dados Genéticas , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Olho/crescimento & desenvolvimento
5.
BMC Med Genomics ; 12(1): 113, 2019 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362747

RESUMO

BACKGROUND: Population studies suggest that genetic factors play an important role in refractive error development; however, the precise role of genetic background and the composition of the signaling pathways underlying refractive eye development remain poorly understood. METHODS: Here, we analyzed normal refractive development and susceptibility to form-deprivation myopia in the eight progenitor mouse strains of the Collaborative Cross (CC). We used RNA-seq to analyze gene expression in the retinae of these mice and reconstruct genetic networks and signaling pathways underlying refractive eye development. We also utilized genome-wide gene-based association analysis to identify mouse genes and pathways associated with myopia in humans. RESULTS: Genetic background strongly influenced both baseline refractive development and susceptibility to environmentally-induced myopia. Baseline refractive errors ranged from - 21.2 diopters (D) in 129S1/svlmj mice to + 22.0 D in CAST/EiJ mice and represented a continuous distribution typical of a quantitative genetic trait. The extent of induced form-deprivation myopia ranged from - 5.6 D in NZO/HILtJ mice to - 20.0 D in CAST/EiJ mice and also followed a continuous distribution. Whole-genome (RNA-seq) gene expression profiling in retinae from CC progenitor strains identified genes whose expression level correlated with either baseline refractive error or susceptibility to myopia. Expression levels of 2,302 genes correlated with the baseline refractive state of the eye, whereas 1,917 genes correlated with susceptibility to induced myopia. Genome-wide gene-based association analysis in the CREAM and UK Biobank human cohorts revealed that 985 of the above genes were associated with myopia in humans, including 847 genes which were implicated in the development of human myopia for the first time. Although the gene sets controlling baseline refractive development and those regulating susceptibility to myopia overlapped, these two processes appeared to be controlled by largely distinct sets of genes. CONCLUSIONS: Comparison with data for other animal models of myopia revealed that the genes identified in this study comprise a well-defined set of retinal signaling pathways, which are highly conserved across different vertebrate species. These results identify major signaling pathways involved in refractive eye development and provide attractive targets for the development of anti-myopia drugs.


Assuntos
Olho/fisiopatologia , Redes Reguladoras de Genes , Miopia/genética , Miopia/fisiopatologia , Refração Ocular/genética , Animais , Cromossomos Humanos/genética , Camundongos de Cruzamento Colaborativo , Olho/crescimento & desenvolvimento , Olho/patologia , Predisposição Genética para Doença , Humanos , Camundongos , Retina/patologia , Retina/fisiopatologia , Transdução de Sinais/genética
6.
Genetics ; 213(2): 581-594, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31467133

RESUMO

Investigating gene expression evolution over micro- and macroevolutionary timescales will expand our understanding of the role of gene expression in adaptation and speciation. In this study, we characterized the evolutionary forces acting on gene expression levels in eye and brain tissue of five Heliconius butterflies with divergence times of ∼5-12 MYA. We developed and applied Brownian motion (BM) and Ornstein-Uhlenbeck (OU) models to identify genes whose expression levels are evolving through drift, stabilizing selection, or a lineage-specific shift. We found that 81% of the genes evolve under genetic drift. When testing for branch-specific shifts in gene expression, we detected 368 (16%) shift events. Genes showing a shift toward upregulation have significantly lower gene expression variance than those genes showing a shift leading toward downregulation. We hypothesize that directional selection is acting in shifts causing upregulation, since transcription is costly. We further uncovered through simulations that parameter estimation of OU models is biased when using small phylogenies and only becomes reliable with phylogenies having ≥ 50 taxa. Therefore, we developed a new statistical test based on BM to identify highly conserved genes (i.e., evolving under strong stabilizing selection), which comprised 3% of the orthoclusters. In conclusion, we found that drift is the dominant evolutionary force driving gene expression evolution in eye and brain tissue in Heliconius Nevertheless, the higher proportion of genes evolving under directional than under stabilizing selection might reflect species-specific selective pressures on vision and the brain that are necessary to fulfill species-specific requirements.


Assuntos
Adaptação Fisiológica/genética , Evolução Molecular , Heliconiaceae/genética , Animais , Encéfalo/crescimento & desenvolvimento , Borboletas/genética , Borboletas/crescimento & desenvolvimento , Olho/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/genética , Deriva Genética , Variação Genética , Heliconiaceae/crescimento & desenvolvimento , Fenótipo , Filogenia , Especificidade da Espécie
7.
PLoS Genet ; 15(7): e1008269, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31299050

RESUMO

Development of eye tissue is initiated by a conserved set of transcription factors termed retinal determination network (RDN). In the fruit fly Drosophila melanogaster, the zinc-finger transcription factor Glass acts directly downstream of the RDN to control identity of photoreceptor as well as non-photoreceptor cells. Tight control of spatial and temporal gene expression is a critical feature during development, cell-fate determination as well as maintenance of differentiated tissues. The molecular mechanisms that control expression of glass, however, remain largely unknown. We here identify complex regulatory mechanisms controlling expression of the glass locus. All information to recapitulate glass expression are contained in a compact 5.2 kb cis-acting genomic element by combining different cell-type specific and general enhancers with repressor elements. Moreover, the immature RNA of the locus contains an alternative small open reading frame (smORF) upstream of the actual glass translation start, resulting in a small peptide instead of the three possible Glass protein isoforms. CRISPR/Cas9-based mutagenesis shows that the smORF is not required for the formation of functioning photoreceptors, but is able to attenuate effects of glass misexpression. Furthermore, editing the genome to generate glass loci eliminating either one or two isoforms shows that only one of the three proteins is critical for formation of functioning photoreceptors, while removing the two other isoforms did not cause defects in developmental or photoreceptor function. Our results show that eye development and function is largely unaffected by targeted manipulations of critical features of the glass transcript, suggesting a strong selection pressure to allow the formation of a functioning eye.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Olho/crescimento & desenvolvimento , Processamento Alternativo , Animais , Diferenciação Celular , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Elementos Facilitadores Genéticos , Olho/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Mutagênese Sítio-Dirigida , Células Fotorreceptoras/metabolismo
8.
Genes (Basel) ; 10(6)2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31207931

RESUMO

Causative genetic variants for more than 30 heritable eye disorders in dogs have been reported. For other clinically described eye disorders, the genetic cause is still unclear. We investigated four Golden Retriever litters segregating for highly variable congenital eye malformations. Several affected puppies had unilateral or bilateral retina dysplasia and/or optic nerve hypoplasia. The four litters shared the same father or grandfather suggesting a heritable condition with an autosomal dominant mode of inheritance. The genome of one affected dog was sequenced and compared to 601 control genomes. A heterozygous private nonsense variant, c.487C>T, was found in the SIX6 gene. This variant is predicted to truncate about a third of the open reading frame, p.(Gln163*). We genotyped all available family members and 464 unrelated Golden Retrievers. All three available cases were heterozygous. Five additional close relatives including the common sire were also heterozygous, but did not show any obvious eye phenotypes. The variant was absent from the 464 unrelated Golden Retrievers and 17 non-affected siblings of the cases. The SIX6 protein is a homeobox transcription factor with a known role in eye development. In humans and other species, SIX6 loss of function variants were reported to cause congenital eye malformations. This strongly suggests that the c.487C>T variant detected contributed to the observed eye malformations. We hypothesize that the residual amount of functional SIX6 protein likely to be expressed in heterozygous dogs is sufficient to explain the observed incomplete penetrance and the varying severity of the eye defects in the affected dogs.


Assuntos
Doenças do Cão/genética , Anormalidades do Olho/genética , Olho/crescimento & desenvolvimento , Proteínas de Homeodomínio/genética , Animais , Códon sem Sentido/genética , Doenças do Cão/fisiopatologia , Cães , Olho/patologia , Anormalidades do Olho/fisiopatologia , Predisposição Genética para Doença , Genoma/genética , Genótipo , Heterozigoto , Humanos
9.
Elife ; 82019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31162046

RESUMO

Epithelial fusion underlies many vital organogenic processes during embryogenesis. Disruptions to these cause a significant number of human birth defects, including ocular coloboma. We provide robust spatial-temporal staging and unique anatomical detail of optic fissure closure (OFC) in the embryonic chick, including evidence for roles of apoptosis and epithelial remodelling. We performed complementary transcriptomic profiling and show that Netrin-1 (NTN1) is precisely expressed in the chick fissure margin during fusion but is immediately downregulated after fusion. We further provide a combination of protein localisation and phenotypic evidence in chick, humans, mice and zebrafish that Netrin-1 has an evolutionarily conserved and essential requirement for OFC, and is likely to have an important role in palate fusion. Our data suggest that NTN1 is a strong candidate locus for human coloboma and other multi-system developmental fusion defects, and show that chick OFC is a powerful model for epithelial fusion research.


Assuntos
Coloboma/genética , Evolução Molecular , Olho/crescimento & desenvolvimento , Netrina-1/genética , Animais , Apoptose/genética , Embrião de Galinha , Galinhas , Coloboma/patologia , Sequência Conservada/genética , Células Epiteliais/metabolismo , Olho/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Camundongos , Palato/crescimento & desenvolvimento , Palato/patologia , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
10.
Invest Ophthalmol Vis Sci ; 60(7): 2623-2630, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31226711

RESUMO

Purpose: To explore the effect of topical atropine on axial eye growth and emmetropization in infant marmosets. Methods: Atropine was applied to one eye from the age of 7 to 56 days in two dose regimens, High (0.1-1% twice daily, increasing with age) or moderate (Mod) (0.1% once daily). Both eyes of the marmosets were refracted, and axial dimensions were measured ultrasonically, at 14, 28, 42, 49, 56, 70, 105, 168, and 279 days of age. The time course of each measured variable was analyzed using multilevel mixed-effects modeling realized in R. Results: The logistic growth curves fitted to anterior segment depth (ASD) did not differ significantly between the dose regimens, but xmid, the age at which growth was half-maximal, and scal, the time constant of the exponential term in the logistic growth curve equation, differed significantly between the ASD of atropinized and untreated eyes (P = 0.03 and P < 0.0001, respectively), with the ASD of atropinized eyes shorter than that of untreated eyes. The splines fitted to lens thickness did not vary significantly with dose, but differed significantly (P < 0.0001) between the atropinized and untreated eyes, with the atropinized lenses thicker. Vitreous chamber depth (VCD) was not significantly different, but the variance of VCD was significantly greater (P < 0.001) in the atropinized compared with the untreated eyes. Refractive error (RE) became relatively myopic in atropinized eyes. The variance of RE in atropinized eyes was significantly greater (P < 0.0001) than in untreated eyes. Conclusions: Atropine caused the infant marmoset lens to move forward and thicken, a relative myopia, and increases in the between-animals variance in VCD, which could be considered a failure of emmetropization.


Assuntos
Atropina/administração & dosagem , Comprimento Axial do Olho/efeitos dos fármacos , Olho/crescimento & desenvolvimento , Antagonistas Muscarínicos/administração & dosagem , Miopia/etiologia , Acomodação Ocular/efeitos dos fármacos , Acomodação Ocular/fisiologia , Administração Oftálmica , Animais , Animais Recém-Nascidos , Callithrix , Emetropia/fisiologia , Masculino , Miopia/fisiopatologia , Soluções Oftálmicas , Retinoscopia , Corpo Vítreo/efeitos dos fármacos
11.
Nutrients ; 11(5)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117180

RESUMO

The aim of this review is to highlight current insights into the roles of choline and docosahexaenoic acid (DHA) in maternal and infant nutrition, with special emphasis on dietary recommendations, gaps in dietary intake, and synergistic implications of both nutrients in infant brain and eye development. Adequate choline and DHA intakes are not being met by the vast majority of US adults, and even more so by women of child-bearing age. Choline and DHA play a significant role in infant brain and eye development, with inadequate intakes leading to visual and neurocognitive deficits. Emerging findings illustrate synergistic interactions between choline and DHA, indicating that insufficient intakes of one or both could have lifelong deleterious impacts on both maternal and infant health.


Assuntos
Encéfalo/crescimento & desenvolvimento , Colina/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Olho/crescimento & desenvolvimento , Fenômenos Fisiológicos da Nutrição do Lactente , Fenômenos Fisiológicos da Nutrição Materna , Feminino , Humanos , Lactente
12.
Proc Biol Sci ; 286(1897): 20182625, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30963847

RESUMO

Increased eye size in animals results in a larger retinal image and thus improves visual acuity. Thus, larger eyes should aid both in finding food as well as detecting predators. On the other hand, eyes are usually very conspicuous and several studies have suggested that eye size is associated with predation risk. However, experimental evidence is scant. In this study, we address how predation affects variation in eye size by performing two experiments using Eurasian perch juveniles as prey and either larger perch or pike as predators. First, we used large outdoor tanks to compare selection due to predators on relative eye size in open and artificial vegetated habitats. Second, we studied the effects of both predation risk and resource levels on phenotypic plasticity in relative eye size in indoor aquaria experiments. In the first experiment, we found that habitat altered selection due to predators, since predators selected for smaller eye size in a non-vegetated habitat, but not in a vegetated habitat. In the plasticity experiment, we found that fish predators induced smaller eye size in males, but not in females, while resource levels had no effect on eye size plasticity. Our experiments provide evidence that predation risk could be one of the driving factors behind variation in eye size within species.


Assuntos
Meio Ambiente , Olho/crescimento & desenvolvimento , Percas/crescimento & desenvolvimento , Comportamento Predatório , Animais , Feminino , Cadeia Alimentar , Masculino , Tamanho do Órgão , Percas/fisiologia , Fatores Sexuais
13.
RNA ; 25(7): 825-839, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30979781

RESUMO

Drosophila Belle (human ortholog DDX3) is a conserved DEAD-box RNA helicase implicated in regulating gene expression. However, the molecular mechanisms by which Belle/DDX3 regulates gene expression are poorly understood. Here we performed systematic mutational analysis to determine the contributions of conserved motifs within Belle to its in vivo function. We found that Belle RNA-binding and RNA-unwinding activities and intrinsically disordered regions (IDRs) are required for Belle in vivo function. Expression of Belle ATPase mutants that cannot bind, hydrolyze, or release ATP resulted in dominant toxic phenotypes. Mechanistically, we discovered that Belle up-regulates reporter protein level when tethered to reporter mRNA, without corresponding changes at the mRNA level, indicating that Belle promotes translation of mRNA that it binds. Belle ATPase activity and amino-terminal IDR were required for this translational promotion activity. We also found that ectopic ovary expression of dominant Belle ATPase mutants decreases levels of cyclin proteins, including Cyclin B, without corresponding changes in their mRNA levels. Finally, we found that Belle binds endogenous cyclin B mRNA. We propose that Belle promotes translation of specific target mRNAs, including cyclin B mRNA, in an ATPase activity-dependent manner.


Assuntos
Adenosina Trifosfatases/metabolismo , RNA Helicases DEAD-box/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas Intrinsicamente Desordenadas/metabolismo , RNA Helicases/metabolismo , Processamento Pós-Transcricional do RNA , RNA Mensageiro/metabolismo , Adenosina Trifosfatases/genética , Animais , Ciclina B/genética , Ciclina B/metabolismo , RNA Helicases DEAD-box/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Olho/crescimento & desenvolvimento , Olho/metabolismo , Feminino , Infertilidade Feminina , Infertilidade Masculina , Proteínas Intrinsicamente Desordenadas/genética , Masculino , Fenótipo , RNA Helicases/genética , RNA Mensageiro/genética
14.
Nat Cell Biol ; 21(4): 420-429, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30936473

RESUMO

During mouse postnatal eye development, the embryonic hyaloid vascular network regresses from the vitreous as an adaption for high-acuity vision. This process occurs with precisely controlled timing. Here, we show that opsin 5 (OPN5; also known as neuropsin)-dependent retinal light responses regulate vascular development in the postnatal eye. In Opn5-null mice, hyaloid vessels regress precociously. We demonstrate that 380-nm light stimulation via OPN5 and VGAT (the vesicular GABA/glycine transporter) in retinal ganglion cells enhances the activity of inner retinal DAT (also known as SLC6A3; a dopamine reuptake transporter) and thus suppresses vitreal dopamine. In turn, dopamine acts directly on hyaloid vascular endothelial cells to suppress the activity of vascular endothelial growth factor receptor 2 (VEGFR2) and promote hyaloid vessel regression. With OPN5 loss of function, the vitreous dopamine level is elevated and results in premature hyaloid regression. These investigations identify violet light as a developmental timing cue that, via an OPN5-dopamine pathway, regulates optic axis clearance in preparation for visual function.


Assuntos
Dopamina/metabolismo , Olho/irrigação sanguínea , Luz , Proteínas de Membrana/metabolismo , Opsinas/metabolismo , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Endotélio Vascular/metabolismo , Olho/enzimologia , Olho/crescimento & desenvolvimento , Olho/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Opsinas/genética , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/efeitos da radiação , Treonina/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/fisiologia , Corpo Vítreo/metabolismo
15.
Exp Eye Res ; 184: 172-182, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31018118

RESUMO

Experiments employing monochromatic light have been used to investigate the role of longitudinal chromatic aberration (LCA) as possible signals for emmetropization for many years. LCA arising from the dispersion of light, causes differences in the focal length at different wavelengths and can impose defocus (wavelength defocus). Short-wavelength light focuses with a shorter focal length than long-wavelength light and, as such, would be expected to produce a smaller, more hyperopic eye. Emmetropization can respond to wavelength defocus since animals reared in monochromatic light adjust their refractive state relative to that measured in white light. In many species, animals reared in monochromatic light respond as predicted by wavelength defocus, becoming more hyperopic in blue light and more myopic in red light. However, tree shrews and rhesus monkey become more hyperopic in red light, and while tree shrews initially become more hyperopic in blue light, they later become more myopic. This review examines the experiments performed in monochromatic light and highlights the potential differences in protocols affecting the results, including experiment duration, circadian rhythm stimulation, light intensity, bandwidth, humoral factors and temporal sensitivity.


Assuntos
Emetropia/fisiologia , Olho/crescimento & desenvolvimento , Luz , Miopia/fisiopatologia , Fenômenos Fisiológicos Oculares , Animais , Refração Ocular/fisiologia , Retina/fisiopatologia , Retina/efeitos da radiação
16.
Cell Prolif ; 52(3): e12593, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30847993

RESUMO

OBJECTIVES: The evolutionary conserved JNK pathway plays crucial role in cell death, yet factors that modulate this signalling have not been fully disclosed. In this study, we aim to identify additional factors that regulate JNK signalling in cell death, and characterize the underlying mechanisms. MATERIALS AND METHODS: Drosophila were raised on standard media, and cross was carried out at 25°C. The Gal4/UAS system was used to express proteins or RNAi in a specific temporal and spatial pattern. Gene expression was revealed by GFP fluorescence, X-gal staining or immunostaining of 3rd instar larval eye and wing discs. Cell death was visualized by acridine orange (AO) staining. Images of fly eyes and wings were taken by OLYMPUS microscopes. RESULTS: We found that licorne (lic) encoding the Drosophila MKK3 is an essential regulator of JNK-mediated cell death. Firstly, loss of lic suppressed ectopic Egr-triggered JNK activation and cell death in eye and wing development. Secondary, lic is necessary for loss-of-cell polarity-induced, physiological JNK-dependent cell death in wing development. Thirdly, Lic overexpression is sufficient to initiate JNK-mediated cell death in developing eyes and wings. Furthermore, ectopic Lic activates JNK signalling by promoting JNK phosphorylation. Finally, genetic epistatic analysis confirmed that Lic acts in parallel with Hep in the Egr-JNK pathway. CONCLUSIONS: This study not only identified Lic as a novel component of the JNK signalling, but also disclosed the crucial roles and mechanism of Lic in cell death.


Assuntos
Morte Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Quinases/metabolismo , Animais , Animais Geneticamente Modificados , Morte Celular/genética , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Epistasia Genética , Olho/crescimento & desenvolvimento , Olho/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genes de Insetos , Sistema de Sinalização das MAP Quinases/genética , Proteínas de Membrana/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Proteínas Quinases/genética , Interferência de RNA , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo
17.
Ecotoxicol Environ Saf ; 175: 164-172, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30897415

RESUMO

Polychlorinated biphenyls (PCBs), a class of persistent organic pollutant, are closely related to abnormal eye development in children. However, little is known regarding the role of peptides in the development of PCB-induced ocular dysplasia. To characterize the nature of PCB exposure on peptides involved in the development of the ocular system, we used liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) to detect differential expression of peptides between normal and PCB-exposed zebrafish embryos. A total of 7900 peptides were analyzed, 90 of which were differentially expressed, with 29 being up-regulated and 61 down-regulated. These peptides were investigated using ingenuity pathway analysis (IPA) and gene ontology (GO) analysis to explore their role in eye development. This study identified 18 peptides associated with the development of the optic nerve and ocular system in the PCB-exposure group, as well as 10 peptides that are located in the functional domain of their precursor proteins. These peptides provide potential biomarkers for the treatment of ocular dysplasia caused by PCBs and may help us understand the mechanism of abnormal eye development caused by organic pollutants.


Assuntos
Exposição Ambiental , Poluentes Ambientais/efeitos adversos , Olho/efeitos dos fármacos , Peptídeos/metabolismo , Bifenilos Policlorados/efeitos adversos , Animais , Biomarcadores/metabolismo , Criança , Cromatografia Líquida , Olho/crescimento & desenvolvimento , Humanos , Espectrometria de Massas em Tandem , Peixe-Zebra
18.
Curr Top Dev Biol ; 132: 351-393, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30797514

RESUMO

This chapter provides an overview of the early developmental origins of six ocular tissues: the cornea, lens, ciliary body, iris, neural retina, and retina pigment epithelium. Many of these tissue types are concurrently specified and undergo a complex set of morphogenetic movements that facilitate their structural interconnection. Within the context of vertebrate eye organogenesis, we also discuss the genetic hierarchies of transcription factors and signaling pathways that regulate growth, patterning, cell type specification and differentiation.


Assuntos
Olho/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Organogênese/genética , Fatores de Transcrição/genética , Animais , Corpo Ciliar/embriologia , Corpo Ciliar/crescimento & desenvolvimento , Corpo Ciliar/metabolismo , Córnea/embriologia , Córnea/crescimento & desenvolvimento , Córnea/metabolismo , Olho/embriologia , Olho/crescimento & desenvolvimento , Humanos , Cristalino/embriologia , Cristalino/crescimento & desenvolvimento , Cristalino/metabolismo , Retina/embriologia , Retina/crescimento & desenvolvimento , Retina/metabolismo , Fatores de Transcrição/metabolismo
19.
BMC Vet Res ; 15(1): 57, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744622

RESUMO

BACKGROUND: Organophosphate pesticides-OP-, like malathion, can alter the normal functioning of neuro-endocrine systems (e.g., hypothalamus-pituitary-thyroid-HPT- axis), and to interfere on the thyroidal homeostasis. Through direct interactions with thyroid receptors, an/or indirectly via up-stream signalling pathways, from the HPT axis (i.e., negative feedback regulation), malathion possess the ability to affect integrity of thyroidal follicular tissue, and it can also block or delay its hormonal functioning. This insecticide can alter the majority of the ontogenetic processes, inducing several deformities, and also provoking decreases in the growth and survival patterns. The present study has been performed to determine the sublethal effects of malathion during the first month of life of the Senegalese sole, Solea senegalensis, and it is mainly focused on the metamorphosis phase. Different transcript expression levels (i.e. thyroid receptors, matrix and bone -Gla-proteins) and immunohistochemical patterns (i.e. thyroid hormones, osteocalcin, cell proliferation) have been analysed during the most critical phases of the flatfish metamorphosis, that is, through differentiation of thyroid system and skeletal development, migration of the eye, and further adaptation to benthic behaviours. RESULTS: In early life stages of the Senegalese sole, the exposure to the highest concentration of malathion (6.25 µg/L) affected to the growth patterns, showing the exposed individuals, a reduction around 60 and 92% of the total length and the dry weigth, respectively. In paralell, a significant reduction of the thyroid follicles (i.e., size and number) it was also been recorded, in a dose-dependent way. Abnormal phenotypes induced in the exposed larvae, did not complete the process of metamorphosis, and displayed several morphological abnormalities and developmental disorders, which were mainly associated with the eye migration process, and with thyroidal and skeletal disorders (i.e., transcriptional and protein changes of thyroid hormones and receptors, and of matrix and bone Gla proteins distribution), that conduced to an inadequate adaptation to the benthic life. CONCLUSIONS: In the Senegalese sole, the majority of the ontogenetic alterations induced by the exposure to malathion were mainly associated to the metamorphosis period, which is a thyroid-driven proccess. In fact, most crucial and transitional ontogenic events, appeared notably disturbed, for e.g., thyroid gland differentiation and functioning, migration of eye, skeletal development and benthonic behaviors.


Assuntos
Doenças dos Peixes/induzido quimicamente , Linguados/crescimento & desenvolvimento , Inseticidas/toxicidade , Malation/toxicidade , Glândula Tireoide/efeitos dos fármacos , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Olho/efeitos dos fármacos , Olho/crescimento & desenvolvimento , Linguados/anormalidades , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Metamorfose Biológica/efeitos dos fármacos , Doenças da Glândula Tireoide/induzido quimicamente , Doenças da Glândula Tireoide/veterinária , Glândula Tireoide/crescimento & desenvolvimento
20.
Mech Dev ; 155: 48-59, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30625369

RESUMO

slc7a5 (also known as LAT1), largely accepted as an amino acid transporter, has been shown to play important roles in cancer and developmental processes. Because knockout mice of Slc7a5 are embryonically lethal due to placental defects, it is difficult to evaluate its role in early development. In this study, expression and function of slc7a5 were evaluated in Xenopus laevis embryos that develop without a placenta. Expression of slc7a5 was detected in the notochord and in the eye and it was not co-localized with slc3a2, which helps slc7a5 to localize at the plasma membrane, before the late neurula stage. Loss-of-function experiment with a morpholino antisense oligonucleotide led to defect of neural and non-neural patterning, inhibition of primary neurogenesis, and disruption of eye development. Disruption of neural development and primary neurogenesis was likely due to impaired notochord development as sonic hedgehog (shh) signaling pathway was compromised in slc7a5-inhibited embryos. These results suggest that slc7a5 is required for notochord development and subsequent primary neurogenesis via shh/gli signaling and for eye development. These novel developmental roles of slc7a5 appeared to be independent of transport function at least before the late neurula stage.


Assuntos
Olho/crescimento & desenvolvimento , Olho/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Notocorda/crescimento & desenvolvimento , Notocorda/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus laevis/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas Hedgehog/metabolismo , Humanos , Neurogênese/fisiologia , Transdução de Sinais/fisiologia
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