scholarly journals Role of Wnt Signaling During In-Vitro Bovine Blastocyst Development and Maturation in Synergism with PPARδ Signaling

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 923
Author(s):  
Tabinda Sidrat ◽  
Abdul Aziz Khan ◽  
Muhammad Idrees ◽  
Myeong-Don Joo ◽  
Lianguang Xu ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Wnt Signaling ◽  
Cellular Proliferation ◽  
Developmental Process ◽  
Critical Role ◽  
Acid Oxidation ◽  
Cell Renewal ◽  
Blastocyst Development ◽  
Bovine Blastocyst

Wnt/β-catenin signaling plays vital role in the regulation of cellular proliferation, migration, stem cells cell renewal and genetic stability. This pathway is crucial during the early developmental process; however, the distinct role of Wnt/β-catenin signaling during pre-implantation period of bovine embryonic development is obscure. Here, we evaluated the critical role of Wnt/β-catenin pathway in the regulation of bovine blastocyst (BL) development and hatching. 6 bromoindurbin-3’oxime (6-Bio) was used to stimulate the Wnt signaling. Treatment with 6-Bio induced the expression of peroxisome proliferator-activated receptor-delta (PPARδ). Interestingly, the PPARδ co-localized with β-catenin and form a complex with TCF/LEF transcription factor. This complex potentiated the expression of several Wnt directed genes, which regulate early embryonic development. Inhibition of PPARδ with selective inhibitor 4-chloro-N-(2-{[5-trifluoromethyl]-2-pyridyl]sulfonyl}ethyl)benzamide (Gsk3787) severely perturbed the BL formation and hatching. The addition of Wnt agonist successfully rescued the BL formation and hatching ability. Importantly, the activation of PPARδ expression by Wnt stimulation enhanced cell proliferation and fatty acid oxidation (FAO) metabolism to improve BL development and hatching. In conclusion, our study provides the evidence that Wnt induced PPARδ expression co-localizes with β-catenin and is a likely candidate of canonical Wnt pathway for the regulation of bovine embryonic development.

scholarly journals Wnt Signaling in Leukemia and Its Bone Marrow Microenvironment

2020 ◽  
Vol 21 (17) ◽  
pp. 6247
Author(s):  
Yongsheng Ruan ◽  
Hye Na Kim ◽  
Heather Ogana ◽  
Yong-Mi Kim
Keyword(s):  
Stem Cells ◽  
Wnt Signaling ◽  
Stromal Cells ◽  
Critical Role ◽  
Neoplastic Disease ◽  
Leukemic Stem Cells ◽  
Hematopoietic Stem ◽  
Disease Therapy ◽  
Wnt Pathways

Leukemia is an aggressive hematologic neoplastic disease. Therapy-resistant leukemic stem cells (LSCs) may contribute to the relapse of the disease. LSCs are thought to be protected in the leukemia microenvironment, mainly consisting of mesenchymal stem/stromal cells (MSC), endothelial cells, and osteoblasts. Canonical and noncanonical Wnt pathways play a critical role in the maintenance of normal hematopoietic stem cells (HSC) and LSCs. In this review, we summarize recent findings on the role of Wnt signaling in leukemia and its microenvironment and provide information on the currently available strategies for targeting Wnt signaling.

scholarly journals Peroxisome Metabolism in Cancer

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1692 ◽  
Author(s):  
Jung-Ae Kim
Keyword(s):  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Cell Metabolism ◽  
Critical Role ◽  
Acid Oxidation ◽  
Metabolic Dysregulation ◽  
Human Disorders ◽  
Peroxisomal Function ◽  
Target Cancer

Peroxisomes are metabolic organelles involved in lipid metabolism and cellular redoxbalance. Peroxisomal function is central to fatty acid oxidation, ether phospholipid synthesis, bile acidsynthesis, and reactive oxygen species homeostasis. Human disorders caused by genetic mutations inperoxisome genes have led to extensive studies on peroxisome biology. Peroxisomal defects are linkedto metabolic dysregulation in diverse human diseases, such as neurodegeneration and age-relateddisorders, revealing the significance of peroxisome metabolism in human health. Cancer is a diseasewith metabolic aberrations. Despite the critical role of peroxisomes in cell metabolism, the functionaleects of peroxisomes in cancer are not as well recognized as those of other metabolic organelles,such as mitochondria. In addition, the significance of peroxisomes in cancer is less appreciated thanit is in degenerative diseases. In this review, I summarize the metabolic pathways in peroxisomesand the dysregulation of peroxisome metabolism in cancer. In addition, I discuss the potential ofinactivating peroxisomes to target cancer metabolism, which may pave the way for more eectivecancer treatment.

scholarly journals Neddylation is critical to cortical development by regulating Wnt/β-catenin signaling

2020 ◽  
Vol 117 (42) ◽  
pp. 26448-26459 ◽  
Author(s):  
Lei Zhang ◽  
Hongyang Jing ◽  
Haiwen Li ◽  
Wenbing Chen ◽  
Bin Luo ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Protein Modification ◽  
Radial Glia ◽  
Critical Role ◽  
Cortical Development ◽  
Nuclear Accumulation ◽  
Progressive Reduction ◽  
Intermediate Progenitors

Wnt signaling plays a critical role in production and differentiation of neurons and undergoes a progressive reduction during cortical development. However, how Wnt signaling is regulated is not well understood. Here we provide evidence for an indispensable role of neddylation, a ubiquitylation-like protein modification, in inhibiting Wnt/β-catenin signaling. We show that β-catenin is neddylated; and inhibiting β-catenin neddylation increases its nuclear accumulation and Wnt/β-catenin signaling. To test this hypothesis in vivo, we mutated Nae1, an obligative subunit of the E1 for neddylation in cortical progenitors. The mutation leads to eventual reduction in radial glia progenitors (RGPs). Consequently, the production of intermediate progenitors (IPs) and neurons is reduced, and neuron migration is impaired, resulting in disorganization of the cerebral cortex. These phenotypes are similar to those of β-catenin gain-of-function mice. Finally, suppressing β-catenin expression is able to rescue deficits of Nae1 mutant mice. Together, these observations identified a mechanism to regulate Wnt/β-catenin signaling in cortical development.

scholarly journals Wnt signaling in kidney: the initiator or terminator?

2020 ◽  
Vol 98 (11) ◽  
pp. 1511-1523 ◽  
Author(s):  
Ping Meng ◽  
Mingsheng Zhu ◽  
Xian Ling ◽  
Lili Zhou
Keyword(s):  
Cell Differentiation ◽  
Embryonic Development ◽  
Wnt Signaling ◽  
Tissue Repair ◽  
Progenitor Cell ◽  
Kidney Development ◽  
Kidney Diseases ◽  
Electrolyte Balance ◽  
Tissue Repair And Regeneration

Abstract The kidney is a key organ in the human body that excretes toxins and sustains the water–electrolyte balance. During embryonic development and disease progression, the kidney undergoes enormous changes in macrostructure, accompanied by a variety of microstructural histological changes, such as glomerular formation and sclerosis, tubule elongation and atrophy, interstitial establishment, and fibrosis progression. All of these rely on the frequent occurrence of cell death and growth. Notably, to overcome disease, some cells regenerate through self-repair or progenitor cell differentiation. However, the signaling mechanisms underlying kidney development and regeneration have not been elucidated. Recently, Wnt signaling has been noted to play an important role. Although it is a well-known developmental signal, the role of Wnt signaling in kidney development and regeneration is not well recognized. In this review, we review the role of Wnt signaling in kidney embryonic development, tissue repair, cell division, and progenitor cell differentiation after injury. Moreover, we briefly highlight advances in our understanding of the pathogenic mechanisms of Wnt signaling in mediating cellular senescence in kidney parenchymal and stem cells, an irreversible arrest of cell proliferation blocking tissue repair and regeneration. We also highlight the therapeutic targets of Wnt signaling in kidney diseases and provide important clues for clinical strategies.

scholarly journals Haemocytes are critical for Drosophila melanogaster post-embryonic development, independent of control of the microbiota

2021 ◽  
Author(s):  
Holly N Stephenson ◽  
Robert Streeck ◽  
Alf Herzig
Keyword(s):  
Embryonic Development ◽  
Adult Development ◽  
Critical Role ◽  
Rna Seq ◽  
Genetic Rescue ◽  
Germ Free ◽  
Drosophila Model ◽  
Axenic Conditions ◽  
Driver Line

Proven roles for haemocytes (blood cells) have expanded beyond the control of infections in Drosophila. Despite this, the critical role of haemocytes in post-embryonic development has long been thought to be limited to control of microorganisms during metamorphosis. This has previously been shown by rescue of adult development in haemocyte-ablation models under germ-free conditions. Here we show that haemocytes have a critical role in post-embryonic development beyond their ability to control the microbiota. Using a newly generated, strong haemocyte-specific driver line for the GAL4/UAS system, we show that specific ablation of haemocytes is pupal lethal, even under axenic conditions. Genetic rescue experiments prove that this is a haemocyte-specific phenomena. RNA-seq data suggests that dysregulation of the midgut is a critical consequence of haemocyte ablation. We believe this novel role of haemocytes during metamorphosis is a major finding for the field. This is an exciting new Drosophila model to study the precise mechanisms in which haemocytes regulate tissue development, findings from which could have far reaching implications beyond invertebrate biology.

scholarly journals COX-2 Silencing in Canine Malignant Melanoma Inhibits Malignant Behaviour

2021 ◽  
Vol 8 ◽  
Author(s):  
Tatiany L. Silveira ◽  
Lisa Y. Pang ◽  
Alexandra Di Domenico ◽  
Emerson S. Veloso ◽  
Istéfani L. D. Silva ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Critical Role ◽  
Micro Rna ◽  
Migration And Invasion ◽  
Melanoma Progression ◽  
Oral Melanoma ◽  
Regulated Expression ◽  
Cox 2 ◽  
Canine Melanoma

Metastatic melanoma is a very aggressive form of cancer in both humans and dogs. Dogs primarily develop oral melanoma of mucosal origin. Although oral melanoma in humans is rare, both diseases are highly aggressive with frequent metastases. This disease represents a “One Health” opportunity to improve molecular and mechanistic understanding of melanoma progression. Accumulating evidence suggests that cyclooxygenase-2 (COX-2) may play a critical role in the malignant behaviour of melanoma. In this study we analysed 85 histologically confirmed melanomas from canine patients and showed that COX-2 is overexpressed in both oral and cutaneous melanomas and that COX-2 expression correlates with established markers of poor prognosis. To determine the role of COX-2 in melanoma we developed two melanoma cell lines with stable integration of an inducible doxycycline-regulated expression vector containing a COX-2 targeted micro-RNA (miRNA). Using this system, we showed that cellular proliferation, migration and invasion are COX-2 dependent, establishing a direct relationship between COX-2 expression and malignant behaviour in canine melanoma. We have also developed a powerful molecular tool to aid further dissection of the mechanisms by which COX-2 regulates melanoma progression.

Evidence for a critical role for the cytoplasmic region of the interleukin 2 (IL-2) receptor gamma chain in IL-2, IL-4, and IL-7 signalling

1994 ◽  
Vol 14 (8) ◽  
pp. 5433-5440
Author(s):  
A Kawahara ◽  
Y Minami ◽  
T Taniguchi
Keyword(s):  
Cellular Proliferation ◽  
Critical Role ◽  
Gene Activation ◽  
Interleukin 2 ◽  
Selective Inhibition ◽  
Cell Interior ◽  
Gamma Chain ◽  
Cytoplasmic Region ◽  
Hematopoietic Cell Line

The high-affinity interleukin 2 receptor (IL-2R) consists of at least three distinct subunits: the IL-2R alpha chain (IL-2R alpha), beta chain (IL-2R beta), and gamma chain (IL-2R gamma). It has been shown that the cytoplasmic region of IL-2R beta, but not of IL-2R alpha, is essential for IL-2 signalling to the cell interior. In the present study, we examined the functional role of the IL-2R gamma cytoplasmic region in the IL-3-dependent mouse hematopoietic cell line BAF-B03, which expresses the endogenous IL-2R alpha and IL-2R gamma, or its subline F7, which additionally expresses human IL-2R beta cDNA. We show that overexpression of a mutant IL-2R gamma, lacking all but 7 amino acids of its cytoplasmic region, results in the selective inhibition of IL-2-induced c-fos gene activation and cellular proliferation in F7 cells. When two chimeric receptor molecules in which the cytoplasmic regions of IL-2R beta and IL-2R gamma had been swapped with each other (IL-2R beta/gamma and IL-2R gamma/beta) were coexpressed in BAF-B03, the cells responded to IL-2. These results indicate the critical importance of the IL-2-induced functional cooperation of the two cytoplasmic regions. Finally, we provide evidence that the IL-2R gamma cytoplasmic region is also critical for the IL-4 and IL-7-induced growth signal transduction in BAF-B03.

scholarly journals An Essential Role of the Cysteine-rich Domain of FZD4 in Norrin/Wnt Signaling and Familial Exudative Vitreoretinopathy

2010 ◽  
Vol 286 (12) ◽  
pp. 10210-10215 ◽  
Author(s):  
Kang Zhang ◽  
Yuko Harada ◽  
Xinran Wei ◽  
Dhananjay Shukla ◽  
Anand Rajendran ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Wnt Pathway ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Peripheral Retina ◽  
Familial Exudative Vitreoretinopathy ◽  
Rich Domain ◽  
Cysteine Rich Domain

The Wnt pathway plays important yet diverse roles in health and disease. Mutations in the Wnt receptor FZD4 gene have been confirmed to cause familial exudative vitreoretinopathy (FEVR). FEVR is characterized by incomplete vascularization of the peripheral retina, which can lead to vitreous bleeding, tractional retinal detachment, and blindness. We screened for mutations in the FZD4 gene in five families with FEVR and identified five mutations (C45Y, Y58C, W226X, C204R, and W496X), including three novel mutations (C45Y, Y58C, and W226X). In the retina, Norrin serves as a ligand and binds to FZD4 to activate the Wnt signaling pathway in normal angiogenesis and vascularization. The cysteine-rich domain (CRD) of FZD4 has been shown to play a critical role in Norrin-FZD4 binding. We investigated the effect of mutations in the FZD4 CRD in Norrin binding and signaling in vitro and in vivo. Wild-type and mutant FZD4 proteins were assayed for Norrin binding and Norrin-dependent activation of the canonical Wnt pathway by cell-surface and overlay binding assays and luciferase reporter assays. In HEK293 transfection studies, C45Y, Y58C, and C204R mutants did not bind to Norrin and failed to transduce FZD4-mediated Wnt/β-catenin signaling. In vivo studies using Xenopus embryos showed that these FZD4 mutations disrupt Norrin/β-catenin signaling as evidenced by decreased Siamois and Xnr3 expression. This study identified a new class of FZD4 gene mutations in human disease and demonstrates a critical role of the CRD in Norrin binding and activation of the β-catenin pathway.

scholarly journals Dynamics of microRNA expression during mouse prenatal development

2018 ◽  
Author(s):  
Sorena Rahmanian ◽  
Rabi Murad ◽  
Alessandra Breschi ◽  
Weihua Zeng ◽  
Mark Mackiewicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Embryonic Development ◽  
Mirna Expression ◽  
Messenger Rna ◽  
Time Course ◽  
Expression Patterns ◽  
Critical Role ◽  
Prenatal Development ◽  
Specific Expression

ABSTRACTMicroRNAs (miRNAs) play a critical role as post-transcriptional regulators of gene expression. The ENCODE project profiled the expression of miRNAs in a comprehensive set of tissues during a time-course of mouse embryonic development and captured the expression dynamics of 785 miRNAs. We found distinct tissue and developmental stage specific miRNA expression clusters, with an overall pattern of increasing tissue specific expression as development proceeds. Comparative analysis of conserved miRNAs in mouse and human revealed stronger clustering of expression patterns by tissue types rather than by species. An analysis of messenger RNA gene expression clusters compared with miRNA expression clusters identifies the potential role of specific miRNA expression clusters in suppressing the expression of mRNAs specific to other developmental programs in the tissue where these microRNAs are expressed during embryonic development. Our results provide the most comprehensive timecourse of miRNA expression as an integrated part of the ENCODE reference dataset for mouse embryonic development.

scholarly journals Evidence for a critical role for the cytoplasmic region of the interleukin 2 (IL-2) receptor gamma chain in IL-2, IL-4, and IL-7 signalling.

1994 ◽  
Vol 14 (8) ◽  
pp. 5433-5440 ◽  
Author(s):  
A Kawahara ◽  
Y Minami ◽  
T Taniguchi
Keyword(s):  
Cellular Proliferation ◽  
Critical Role ◽  
Gene Activation ◽  
Interleukin 2 ◽  
Selective Inhibition ◽  
Cell Interior ◽  
Gamma Chain ◽  
Cytoplasmic Region ◽  
Hematopoietic Cell Line

The high-affinity interleukin 2 receptor (IL-2R) consists of at least three distinct subunits: the IL-2R alpha chain (IL-2R alpha), beta chain (IL-2R beta), and gamma chain (IL-2R gamma). It has been shown that the cytoplasmic region of IL-2R beta, but not of IL-2R alpha, is essential for IL-2 signalling to the cell interior. In the present study, we examined the functional role of the IL-2R gamma cytoplasmic region in the IL-3-dependent mouse hematopoietic cell line BAF-B03, which expresses the endogenous IL-2R alpha and IL-2R gamma, or its subline F7, which additionally expresses human IL-2R beta cDNA. We show that overexpression of a mutant IL-2R gamma, lacking all but 7 amino acids of its cytoplasmic region, results in the selective inhibition of IL-2-induced c-fos gene activation and cellular proliferation in F7 cells. When two chimeric receptor molecules in which the cytoplasmic regions of IL-2R beta and IL-2R gamma had been swapped with each other (IL-2R beta/gamma and IL-2R gamma/beta) were coexpressed in BAF-B03, the cells responded to IL-2. These results indicate the critical importance of the IL-2-induced functional cooperation of the two cytoplasmic regions. Finally, we provide evidence that the IL-2R gamma cytoplasmic region is also critical for the IL-4 and IL-7-induced growth signal transduction in BAF-B03.

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