scholarly journals Activation of the WNT-BMP-FGF Regulatory Network Induces the Onset of Cell Death in Anterior Mesodermal Cells to Establish the ANZ

2021 ◽  
Vol 9 ◽  
Author(s):  
Martha Elena Díaz-Hernández ◽  
Claudio Iván Galván-Hernández ◽  
Jessica Cristina Marín-Llera ◽  
Karen Camargo-Sosa ◽  
Marcia Bustamante ◽  
...  
Keyword(s):  
Cell Death ◽  
Wnt Signaling ◽  
Regulatory Network ◽  
Feedback Loop ◽  
Anterior Margin ◽  
Bmp Signaling ◽  
Limb Bud ◽  
Digit Number ◽  
Spatiotemporal Control ◽  
Signaling Interactions

The spatiotemporal control of programmed cell death (PCD) plays a significant role in sculpting the limb. In the early avian limb bud, the anterior necrotic zone (ANZ) and the posterior necrotic zone are two cell death regions associated with digit number reduction. In this study, we evaluated the first events triggered by the FGF, BMP, and WNT signaling interactions to initiate cell death in the anterior margin of the limb to establish the ANZ. This study demonstrates that in a period of two to 8 h after the inhibition of WNT or FGF signaling or the activation of BMP signaling, cell death was induced in the anterior margin of the limb concomitantly with the regulation of Dkk, Fgf8, and Bmp4 expression. Comparing the gene expression profile between the ANZ and the undifferentiated zone at 22HH and 25HH and between the ANZ of 22HH and 25HH stages correlates with functional programs controlled by the regulatory network FGF, BMP, and WNT signaling in the anterior margin of the limb. This work provides novel insights to recognize a negative feedback loop between FGF8, BMP4, and DKK to control the onset of cell death in the anterior margin of the limb to the establishment of the ANZ.

scholarly journals The Dickkopf1 and FOXM1 positive feedback loop promotes tumor growth in pancreatic and esophageal cancers

Oncogene ◽  
2021 ◽  
Author(s):  
Hirokazu Kimura ◽  
Ryota Sada ◽  
Naoki Takada ◽  
Akikazu Harada ◽  
Yuichiro Doki ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wnt Signaling ◽  
Cancer Cell ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Ductal Adenocarcinoma ◽  
Cancer Cell Proliferation ◽  
Positive Feedback Loop ◽  
Dkk1 Expression ◽  
Foxm1 Expression

AbstractDickkopf1 (DKK1) is overexpressed in various cancers and promotes cancer cell proliferation by binding to cytoskeleton-associated protein 4 (CKAP4). However, the mechanisms underlying DKK1 expression are poorly understood. RNA sequence analysis revealed that expression of the transcription factor forkhead box M1 (FOXM1) and its target genes concordantly fluctuated with expression of DKK1 in pancreatic ductal adenocarcinoma (PDAC) cells. DKK1 knockdown decreased FOXM1 expression and vice versa in PDAC and esophageal squamous cell carcinoma (ESCC) cells. Inhibition of either the DKK1-CKAP4-AKT pathway or the ERK pathway suppressed FOXM1 expression, and simultaneous inhibition of both pathways showed synergistic effects. A FOXM1 binding site was identified in the 5ʹ-untranslated region of the DKK1 gene, and its depletion decreased DKK1 expression and cancer cell proliferation. Clinicopathological and database analysis revealed that PDAC and ESCC patients who simultaneously express DKK1 and FOXM1 have a poorer prognosis. Multivariate analysis demonstrated that expression of both DKK1 and FOXM1 is the independent prognostic factor in ESCC patients. Although it has been reported that FOXM1 enhances Wnt signaling, FOXM1 induced DKK1 expression independently of Wnt signaling in PDAC and ESCC cells. These results suggest that DKK1 and FOXM1 create a positive feedback loop to promote cancer cell proliferation.

scholarly journals Single nucleotide polymorphisms in Wnt signaling and cell death pathway genes and susceptibility to colorectal cancer

2010 ◽  
Vol 31 (8) ◽  
pp. 1381-1386 ◽  
Author(s):  
B. Frank ◽  
M. Hoffmeister ◽  
N. Klopp ◽  
T. Illig ◽  
J. Chang-Claude ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Single Nucleotide Polymorphisms ◽  
Wnt Signaling ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Cell Death Pathway

BMP4 and WNT signaling interact to promote mouse tracheal mesenchyme morphogenesis

2021 ◽  
Author(s):  
Natalia Bottasso Arias ◽  
Lauren Leesman ◽  
Kaulini Burra ◽  
John Snowball ◽  
Ronak M Shah ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Wnt Signaling ◽  
Rna Sequencing ◽  
Muscle Development ◽  
Target Genes ◽  
Bmp Signaling ◽  
Embryonic Mouse ◽  
Tracheal Cartilage ◽  
Cartilage Formation

Tracheobronchomalacia and Complete Tracheal Rings are congenital malformations of the trachea associated with morbidity and mortality for which the etiology remains poorly understood. Epithelial expression of Wls (a cargo receptor mediating Wnt ligand secretion) by tracheal cells is essential for patterning the embryonic mouse trachea's cartilage and muscle. RNA sequencing indicated that Wls differentially modulated the expression of BMP signaling molecules. We tested whether BMP signaling, induced by epithelial Wnt ligands, mediates cartilage formation. Deletion of Bmp4 from respiratory tract mesenchyme impaired tracheal cartilage formation that was replaced by ectopic smooth muscle, recapitulating the phenotype observed after epithelial deletion of Wls in the embryonic trachea. Ectopic muscle was caused in part by anomalous differentiation and proliferation of smooth muscle progenitors rather than tracheal cartilage progenitors. Mesenchymal deletion of Bmp4 impaired expression of Wnt/β-catenin target genes, including targets of WNTsignaling: Notum, and Axin2. In vitro, rBMP4 rescued the expression of Notum in Bmp4 deficient tracheal mesenchymal cells and induced Notum promoter activity via SMAD1/5. RNA sequencing of Bmp4 deficient tracheas identified genes essential for chondrogenesis and muscle development co-regulated by BMP and WNT signaling. During tracheal morphogenesis, WNT signaling induces Bmp4 in mesenchymal progenitors to promote cartilage differentiation and restrict trachealis muscle. In turn, Bmp4 differentially regulates the expression of Wnt/β-catenin targets to attenuate mesenchymal WNT signaling and to further support chondrogenesis.

FGF-4 maintains polarizing activity of posterior limb bud cells in vivo and in vitro

Development ◽  
1993 ◽  
Vol 119 (1) ◽  
pp. 199-206 ◽  
Author(s):  
A. Vogel ◽  
C. Tickle
Keyword(s):  
Posterior Margin ◽  
Anterior Margin ◽  
Marked Decrease ◽  
Mesenchymal Cells ◽  
Apical Ectodermal Ridge ◽  
Limb Bud ◽  
Posterior Limb ◽  
Vertebrate Limb

The polarizing region is a major signalling tissue involved in patterning the tissues of the vertebrate limb. The polarizing region is located at the posterior margin of the limb bud and can be recognized by its ability to induce additional digits when grafted to the anterior margin of a chick limb bud. The signal from the polarizing region operates at the tip of the bud in the progress zone, a zone of undifferentiated mesenchymal cells, maintained by interactions with the apical ectodermal ridge. A number of observations have pointed to a link between the apical ectodermal ridge and signalling by the polarizing region. To test this possibility, we removed the posterior apical ectodermal ridge of chick wing buds and assayed posterior mesenchyme for polarizing activity. When the apical ectodermal ridge is removed, there is a marked decrease in polarizing activity of posterior cells. The posterior apical ectodermal ridge is known to express FGF-4 and we show that the decrease in polarizing activity of posterior cells of wing buds that normally follows ridge removal can be prevented by implanting a FGF-4-soaked bead. Furthermore, we show that both ectoderm and FGF-4 maintain polarizing activity of limb bud cells in culture.

Oscillatory Behaviors of Delayed p53 Regulatory Network with microRNA 192 in DNA Damage Response

2021 ◽  
Vol 31 (02) ◽  
pp. 2150020
Author(s):  
Chunyan Gao ◽  
Fangqi Chen
Keyword(s):  
Dna Damage ◽  
Time Delay ◽  
Dna Damage Response ◽  
Positive Feedback ◽  
Regulatory Network ◽  
Feedback Loop ◽  
Research Work ◽  
Positive Feedback Loop ◽  
Damage Response ◽  
High Level

This study develops a general model of delayed p53 regulatory network in the DNA damage response by introducing microRNA 192-mediated positive feedback loop based on the existing research work. Through theoretical analysis and numerical simulation, we find that the delay as a bifurcation parameter can drive the p53-Mdm2 module to undergo a supercritical Hopf bifurcation, thereby producing oscillation behavior. Moreover, we demonstrate how the positive feedback loop formed by p53* and microRNA 192 (miR-192) with the feature of double-negative regulation produces oscillations. Further, a comparison is given to demonstrate that microRNA 192-mediated positive feedback loop affects the robustness of system oscillations. In addition, we show that ataxia telangiectasia mutated kinase (ATM), once activated by DNA damage, makes p53* undergo two Hopf bifurcations. These results reveal that both time delay and miR-192 play tumor suppressing roles by promoting p53 oscillation or high level expression, which will provide a perspective for promoting the development of anti-cancer drugs by targeting miR-192 and time delay.

Positional signalling by Hensen's node when grafted to the chick limb bud

Development ◽  
1986 ◽  
Vol 94 (1) ◽  
pp. 257-265
Author(s):  
Amata Hornbruch ◽  
Lewis Wolpert
Keyword(s):  
Anterior Margin ◽  
Early Embryo ◽  
Limb Bud ◽  
Stage 4 ◽  
The Future

Hensen's node from stage 4 to stage 10 shows polarizing activity when grafted to the anterior margin of the chick limb bud. It can specify additional digits though its action is somewhat attenuated when compared with the effect of a grafted polarizing region. At stage 10 the activity disappears from the node and is found both posterior to the node and in the future wing region of the flank. The ability of Hensen's node to generate a positional signal suggests that the signal in the limb and early embryo may be similar. The results support the view of the polarizing region as a discrete signalling region.

scholarly journals Systematic Dissection of the Evolutionarily Conserved WetA Developmental Regulator across a Genus of Filamentous Fungi

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Ming-Yueh Wu ◽  
Matthew E. Mead ◽  
Mi-Kyung Lee ◽  
Erin M. Ostrem Loss ◽  
Sun-Chang Kim ◽  
...  
Keyword(s):  
Gene Regulatory Network ◽  
Filamentous Fungi ◽  
Negative Feedback ◽  
Regulatory Network ◽  
Feedback Loop ◽  
Spore Formation ◽  
Negative Feedback Loop ◽  
Content Type ◽  
Asexual Sporulation ◽  
Gene Regulatory

ABSTRACTAsexual sporulation is fundamental to the ecology and lifestyle of filamentous fungi and can facilitate both plant and human infection. InAspergillus, the production of asexual spores is primarily governed by the BrlA→AbaA→WetA regulatory cascade. The final step in this cascade is controlled by the WetA protein and governs not only the morphological differentiation of spores but also the production and deposition of diverse metabolites into spores. While WetA is conserved across the genusAspergillus, the structure and degree of conservation of thewetAgene regulatory network (GRN) remain largely unknown. We carried out comparative transcriptome analyses of comparisons betweenwetAnull mutant and wild-type asexual spores in three representative species spanning the diversity of the genusAspergillus:A. nidulans,A. flavus, andA. fumigatus. We discovered that WetA regulates asexual sporulation in all three species via a negative-feedback loop that represses BrlA, the cascade’s first step. Furthermore, data from chromatin immunoprecipitation sequencing (ChIP-seq) experiments inA. nidulansasexual spores suggest that WetA is a DNA-binding protein that interacts with a novel regulatory motif. Several global regulators known to bridge spore production and the production of secondary metabolites show species-specific regulatory patterns in our data. These results suggest that the BrlA→AbaA→WetA cascade’s regulatory role in cellular and chemical asexual spore development is functionally conserved but that thewetA-associated GRN has diverged duringAspergillusevolution.IMPORTANCEThe formation of resilient spores is a key factor contributing to the survival and fitness of many microorganisms, including fungi. In the fungal genusAspergillus, spore formation is controlled by a complex gene regulatory network that also impacts a variety of other processes, including secondary metabolism. To gain mechanistic insights into how fungal spore formation is controlled acrossAspergillus, we dissected the gene regulatory network downstream of a major regulator of spore maturation (WetA) in three species that span the diversity of the genus: the genetic modelA. nidulans, the human pathogenA. fumigatus, and the aflatoxin producerA. flavus. Our data show that WetA regulates asexual sporulation in all three species via a negative-feedback loop and likely binds a novel regulatory element that we term the WetA response element (WRE). These results shed light on how gene regulatory networks in microorganisms control important biological processes and evolve across diverse species.

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