scholarly journals Phase transition specified by a binary code patterns the vertebrate eye cup

2021 ◽  
Author(s):  
Revathi Balasubramanian ◽  
Xuanyu Min ◽  
Peter M.J. Quinn ◽  
Quentin Lo Giudice ◽  
Chenqi Tao ◽  
...  
Keyword(s):  
Phase Transition ◽  
Wnt Signaling ◽  
Single Cell Analysis ◽  
Fgf Signaling ◽  
Independent Manner ◽  
Ciliary Margin ◽  
Evolutionarily Conserved ◽  
Human Ips Cells ◽  
Vertebrate Eye

The developing vertebrate eye cup is partitioned into the neural retina (NR), the retinal pigmented epithelium (RPE) and the ciliary margin (CM). By single cell analysis, we showed that a gradient of FGF signaling regulates demarcation and subdivision of the CM and controls its stem cell-like property of self-renewal, differentiation and survival. This regulation by FGF is balanced by an evolutionarily conserved Wnt signaling gradient induced by the lens ectoderm and the periocular mesenchyme, which specifies the CM and the distal RPE. These two morphogen gradients converge in the CM where FGF signaling promotes Wnt signaling by stabilizing β-catenin in a GSK3β-independent manner. We further showed that activation of Wnt signaling converts the NR to either the CM or the RPE depending on the level of FGF signaling. Conversely, activation of FGF transforms the RPE to the NR or CM dependent on Wnt activity. We demonstrated that the default fate of the eye cup is the NR, but synergistic FGF and Wnt signaling promotes CM formation both in vivo and in retinal organoid culture of human iPS cells. Our study reveals that the vertebrate eye develops through phase transition determined by a combinatorial code of FGF and Wnt signaling.

scholarly journals Deficient FGF signaling in the developing peripheral retina disrupts ciliary margin development and causes aniridia

2018 ◽  
Author(s):  
Revathi Balasubramanian ◽  
Chenqi Tao ◽  
Karina Polanco ◽  
Jian Zhong ◽  
Fen Wang ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Critical Role ◽  
Peripheral Retina ◽  
Fgf Signaling ◽  
Surface Ectoderm ◽  
Genetic Ablation ◽  
Central Retina ◽  
Ciliary Margin ◽  
Wnt Ligands

ABSTRACTThe mammalian ciliary margin is a part of the developing peripheral neural retina that differentiates into the ciliary body and the iris. Canonical WNT signaling plays a critical role in the specification of the ciliary margin at the peripheral retina in the presence of strong FGF signaling in the central retina. The mechanism of how the boundary between the central retina and the ciliary margin is created has not been previously elucidated. Using genetic ablation and epistasis experiments, we show that loss of FGF signaling gradient in the peripheral retina causes expansion of WNT signaling towards the central retina thereby disrupting the neurogenic boundary and compartmentalization of the ciliary margin. Loss of WNT signaling displays a complimentary effect with expansion of FGF signaling into the ciliary marginal space. Using in vivo experiments, we elucidate the FGF signaling cascade involved in development of the ciliary margin. We also identify the surface ectoderm as the source of WNT ligands in eliciting WNT response at the ciliary margin. We show that an interaction between FGF and WNT signaling is required for generation of the ciliary marginal cells. Taken together, our results reveal that a gradient intersection of FGF and WNT signaling is required for specification of the ciliary margin.

The Xenopus homologue of the Drosophila gene tailless has a function in early eye development

Development ◽  
1998 ◽  
Vol 125 (13) ◽  
pp. 2425-2432 ◽  
Author(s):  
T. Hollemann ◽  
E. Bellefroid ◽  
T. Pieler
Keyword(s):  
Eye Development ◽  
Neural Plate ◽  
Regulatory Function ◽  
Genetic Circuits ◽  
Optic Stalk ◽  
Drosophila Gene ◽  
Ciliary Margin ◽  
Evolutionarily Conserved ◽  
Optic Cup ◽  
Vertebrate Eye

Genetic circuits responsible for the development of photoreceptive organs appear to be evolutionarily conserved. Here, the Xenopus homologue Xtll of the Drosophila gene tailless (tll), which we find to be expressed during early eye development, is characterized with respect to its relationship to vertebrate regulators of eye morphogenesis, such as Pax6 and Rx. Expression of all three genes is first detected in the area corresponding to the eye anlagen within the open neural plate in partially overlapping, but not identical, patterns. During the evagination of the optic vesicle, Xtll expression is most prominent in the optic stalk, as well as in the distal tip of the forming vesicle. In tadpole-stage embryos, Xtll gene transcription is most prominent in the ciliary margin of the optic cup. Inhibition of Xtll function in Xenopus embryos interferes specifically with the evagination of the eye vesicle and, in consequence, Xpax6 gene expression is severely reduced in such manipulated embryos. These findings suggest that Xtll serves an important regulatory function in the earliest phases of vertebrate eye development.

scholarly journals The microRNA miR-8 is a conserved negative regulator of Wnt signaling

2008 ◽  
Vol 105 (40) ◽  
pp. 15417-15422 ◽  
Author(s):  
Jennifer A. Kennell ◽  
Isabelle Gerin ◽  
Ormond A. MacDougald ◽  
Ken M. Cadigan
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Target Genes ◽  
Wnt Signaling Pathway ◽  
Negative Regulator ◽  
Animal Development ◽  
Protein Levels ◽  
Evolutionarily Conserved ◽  
Multiple Levels

Wnt signaling plays many important roles in animal development. This evolutionarily conserved signaling pathway is highly regulated at all levels. To identify regulators of the Wnt/Wingless (Wg) pathway, we performed a genetic screen in Drosophila. We identified the microRNA miR-8 as an inhibitor of Wg signaling. Expression of miR-8 potently antagonizes Wg signaling in vivo, in part by directly targeting wntless, a gene required for Wg secretion. In addition, miR-8 inhibits the pathway downstream of the Wg signal by repressing TCF protein levels. Another positive regulator of the pathway, CG32767, is also targeted by miR-8. Our data suggest that miR-8 potently antagonizes the Wg pathway at multiple levels, from secretion of the ligand to transcription of target genes. In addition, mammalian homologues of miR-8 promote adipogenesis of marrow stromal cells by inhibiting Wnt signaling. These findings indicate that miR-8 family members play an evolutionarily conserved role in regulating the Wnt signaling pathway.

scholarly journals Elevated CO2 regulates the Wnt signaling pathway in mammals, Drosophila melanogaster and Caenorhabditis elegans

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Masahiko Shigemura ◽  
Emilia Lecuona ◽  
Martín Angulo ◽  
Laura A. Dada ◽  
Melanie B. Edwards ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Caenorhabditis Elegans ◽  
Wnt Signaling ◽  
Large Scale ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Secondary Analysis ◽  
Evolutionarily Conserved ◽  
Integrated Or

AbstractCarbon dioxide (CO2) is sensed by cells and can trigger signals to modify gene expression in different tissues leading to changes in organismal functions. Despite accumulating evidence that several pathways in various organisms are responsive to CO2 elevation (hypercapnia), it has yet to be elucidated how hypercapnia activates genes and signaling pathways, or whether they interact, are integrated, or are conserved across species. Here, we performed a large-scale transcriptomic study to explore the interaction/integration/conservation of hypercapnia-induced genomic responses in mammals (mice and humans) as well as invertebrates (Caenorhabditis elegans and Drosophila melanogaster). We found that hypercapnia activated genes that regulate Wnt signaling in mouse lungs and skeletal muscles in vivo and in several cell lines of different tissue origin. Hypercapnia-responsive Wnt pathway homologues were similarly observed in secondary analysis of available transcriptomic datasets of hypercapnia in a human bronchial cell line, flies and nematodes. Our data suggest the evolutionarily conserved role of high CO2 in regulating Wnt pathway genes.

scholarly journals ΔN-Tp63 mediates Wnt/β-catenin-induced inhibition of differentiation in basal stem cells of mucociliary epithelia

2019 ◽  
Author(s):  
Maximilian Haas ◽  
José Luis Gómez Vázquez ◽  
Dingyuan Iris Sun ◽  
Hong Thi Tran ◽  
Magdalena Brislinger ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wnt Signaling ◽  
Basal Cells ◽  
Cell Hyperplasia ◽  
Chronic Lung Diseases ◽  
Evolutionarily Conserved ◽  
Inhibition Of Differentiation ◽  
Mucociliary Epithelia

SummaryMucociliary epithelia provide a first line of defense against pathogens in the airways and the epidermis of vertebrate larvae. Impaired regeneration and remodeling of mucociliary epithelia are associated with dysregulated Wnt/β-catenin signaling in chronic airway diseases, but underlying mechanisms remain elusive and studies of Wnt signaling in mucociliary cells yield seemingly contradicting results. Employing the Xenopus mucociliary epidermis, the mouse airway, and human airway basal stem cell cultures, we characterize the evolutionarily conserved roles of Wnt/β-catenin signaling in mucociliary cells in vertebrates. Wnt signaling is required in multiciliated cells for cilia formation during differentiation stages, but in Basal cells, Wnt signaling prevents specification and differentiation of epithelial cell types by activating ΔN-TP63 expression. We demonstrate that ΔN-TP63 is a master transcription factor in Basal cells, which is necessary and sufficient to mediate the Wnt-induced inhibition of differentiation and is required to retain basal stem cells during development. Chronic stimulation of Wnt signaling leads to mucociliary remodeling and Basal cell hyperplasia, but this is reversible in vivo and in vitro, suggesting Wnt inhibition as an option in the treatment of chronic lung diseases. Our work sheds light into the evolutionarily conserved regulation of stem cells and differentiation, resolves Wnt functions in mucociliary epithelia, and provides crucial insights into mucociliary development, regeneration and disease mechanisms.

scholarly journals Canonical Wnt Signaling Is Critical to Estrogen-Mediated Uterine Growth

2004 ◽  
Vol 18 (12) ◽  
pp. 3035-3049 ◽  
Author(s):  
Xiaonan Hou ◽  
Yi Tan ◽  
Meiling Li ◽  
Sudhansu K. Dey ◽  
Sanjoy K. Das
Keyword(s):  
Wnt Signaling ◽  
Biological Effects ◽  
Canonical Wnt Signaling ◽  
Mouse Uterus ◽  
Independent Manner ◽  
Uterine Epithelial Cell ◽  
Uterine Growth ◽  
Early Effects ◽  
Canonical Wnt

Abstract Major biological effects of estrogen in the uterus are thought to be primarily mediated by nuclear estrogen receptors, ERα and ERβ. We show here that estrogen in an ER-independent manner rapidly up-regulates the expression of Wnt4 and Wnt5a of the Wnt family and frizzled-2 of the Wnt receptor family in the mouse uterus. One of the mechanisms by which Wnts mediate canonical signaling involves stabilization of intracellular β-catenin. We observed that estrogen treatment prompts nuclear localization of active β-catenin in the uterine epithelium. We also found that adenovirus mediated in vivo delivery of SFRP-2, a Wnt antagonist, down-regulates estrogen-dependent β-catenin activity without affecting some of the early effects (water imbibition and angiogenic markers) and inhibits uterine epithelial cell growth, suggesting that canonical Wnt signaling is critical to estrogen-induced uterine growth. Our present results provide evidence for a novel role of estrogen that targets early Wnt/β-catenin signaling in an ER-independent manner to regulate the late uterine growth response that is ER dependent.

scholarly journals Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jingjing Yang ◽  
Yulu Zhou ◽  
Shuduo Xie ◽  
Ji Wang ◽  
Zhaoqing Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Morphological Changes ◽  
Tumor Model ◽  
Independent Manner ◽  
Regulated Cell Death ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Approved Drugs

Abstract Background Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxidation and is involved in various pathophysiological conditions, including cancer. Targeting ferroptosis is considered to be a novel anti-cancer strategy. The identification of FDA-approved drugs as ferroptosis inducers is proposed to be a new promising approach for cancer treatment. Despite a growing body of evidence indicating the potential efficacy of the anti-diabetic metformin as an anti-cancer agent, the exact mechanism underlying this efficacy has not yet been fully elucidated. Methods The UFMylation of SLC7A11 is detected by immunoprecipitation and the expression of UFM1 and SLC7A11 in tumor tissues was detected by immunohistochemical staining. The level of ferroptosis is determined by the level of free iron, total/lipid Ros and GSH in the cells and the morphological changes of mitochondria are observed by transmission electron microscope. The mechanism in vivo was verified by in situ implantation tumor model in nude mice. Results Metformin induces ferroptosis in an AMPK-independent manner to suppress tumor growth. Mechanistically, we demonstrate that metformin increases the intracellular Fe2+ and lipid ROS levels. Specifically, metformin reduces the protein stability of SLC7A11, which is a critical ferroptosis regulator, by inhibiting its UFMylation process. Furthermore, metformin combined with sulfasalazine, the system xc− inhibitor, can work in a synergistic manner to induce ferroptosis and inhibit the proliferation of breast cancer cells. Conclusions This study is the first to demonstrate that the ability of metformin to induce ferroptosis may be a novel mechanism underlying its anti-cancer effect. In addition, we identified SLC7A11 as a new UFMylation substrate and found that targeting the UFM1/SLC7A11 pathway could be a promising cancer treatment strategy.

scholarly journals Hypoxia promotes the metastasis of pancreatic cancer through regulating NOX4/KDM5A-mediated histone methylation modification changes in a HIF1A-independent manner

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Hongzhen Li ◽  
Chunyan Peng ◽  
Chenhui Zhu ◽  
Shuang Nie ◽  
Xuetian Qian ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Nadph Oxidase ◽  
Western Blot ◽  
Cancer Progression ◽  
Histone Methylation ◽  
Invasion And Metastasis ◽  
Independent Manner ◽  
Nadph Oxidase 4

Abstract Background Hypoxia is a characteristic of the tumor microenvironments within pancreatic cancer (PC), which has been linked to its malignancy. Recently, hypoxia has been reported to regulate the activity of important carcinogenic pathways by changing the status of histone modification. NOX4, a member of NADPH oxidase (NOX), has been found to be activated by hypoxia and promote cancer progression in several cancers. But whether it is involved in the epigenetic changes of tumor cells induced by hypoxia is still unclear, and its biological roles in PC also need to be explored. Methods A hypoxic-related gene signature and its associated pathways in PC were identified by analyzing the pancreatic cancer gene expression data from GEO and TCGA database. Candidate downstream gene (NOX4), responding to hypoxia, was validated by RT-PCR and western blot. Then, we evaluated the relationship between NOX4 expression and clinicopathologic parameters in 56 PC patients from our center. In vitro and in vivo assays were preformed to explore the phenotype of NOX4 in PC. Immunofluorescence, western blot and chromatin immunoprecipitation assays were further applied to search for a detailed mechanism. Results We quantified hypoxia and developed a hypoxia signature, which was associated with worse prognosis and elevated malignant potential in PC. Furthermore, we found that NADPH oxidase 4 (NOX4), which was induced by hypoxia and upregulated in PC in a HIF1A-independent manner, caused inactivation of lysine demethylase 5A (KDM5A), increased the methylation modification of histone H3 and regulated the transcription of EMT-associated gene_ snail family transcriptional repressor 1 (SNAIL1). This served to promote the invasion and metastasis of PC. NOX4 deficiency repressed hypoxia-induced EMT, reduced expression of H3K4ME3 and impaired the invasion and metastasis of PC cells; however, knockdown of KDM5A reversed the poor expression of H3KEME3 induced by NOX4 deficiency, thereby promoting EMT. Conclusions This study highlights the prognostic role of hypoxia-related genes in PC and strong correlation with EMT pathway. Our results also creatively discovered that NOX4 was an essential mediator for hypoxia-induced histone methylation modification and EMT in PC cells.

scholarly journals DNA methylation mediated RSPO2 to promote follicular development in mammals

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Xiaofeng Zhou ◽  
Yingting He ◽  
Nian Li ◽  
Guofeng Bai ◽  
Xiangchun Pan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Methylation Level ◽  
Molecular Mechanisms ◽  
Cpg Island ◽  
Wnt Signaling Pathway ◽  
Follicular Development ◽  
Expression Level

AbstractIn female mammals, the proliferation, apoptosis, and estradiol-17β (E2) secretion of granulosa cells (GCs) have come to decide the fate of follicles. DNA methylation and RSPO2 gene of Wnt signaling pathway have been reported to involve in the survival of GCs and follicular development. However, the molecular mechanisms for how DNA methylation regulates the expression of RSPO2 and participates in the follicular development are not clear. In this study, we found that the mRNA and protein levels of RSPO2 significantly increased during follicular development, but the DNA methylation level of RSPO2 promoter decreased gradually. Inhibition of DNA methylation or DNMT1 knockdown could decrease the methylation level of CpG island (CGI) in RSPO2 promoter and upregulate the expression level of RSPO2 in porcine GCs. The hypomethylation of −758/−749 and −563/−553 regions in RSPO2 promoter facilitated the occupancy of transcription factor E2F1 and promoted the transcriptional activity of RSPO2. Moreover, RSPO2 promoted the proliferation of GCs with increasing the expression level of PCNA, CDK1, and CCND1 and promoted the E2 secretion of GCs with increasing the expression level of CYP19A1 and HSD17B1 and inhibited the apoptosis of GCs with decreasing the expression level of Caspase3, cleaved Caspase3, cleaved Caspase8, cleaved Caspase9, cleaved PARP, and BAX. In addition, RSPO2 knockdown promoted the apoptosis of GCs, blocked the development of follicles, and delayed the onset of puberty with decreasing the expression level of Wnt signaling pathway-related genes (LGR4 and CTNNB1) in vivo. Taken together, the hypomethylation of −758/−749 and −563/−553 regions in RSPO2 promoter facilitated the occupancy of E2F1 and enhanced the transcription of RSPO2, which further promoted the proliferation and E2 secretion of GCs, inhibited the apoptosis of GCs, and ultimately ameliorated the development of follicles through Wnt signaling pathway. This study will provide useful information for further exploration on DNA-methylation-mediated RSPO2 pathway during follicular development.

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