scholarly journals The origin of dorsoventral polarity in Drosophila

2003 ◽  
Vol 358 (1436) ◽  
pp. 1317-1329 ◽  
Author(s):  
Siegfried Roth
Keyword(s):  
Concentration Gradient ◽  
Messenger Rna ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Receptor Activation ◽  
Follicle Cells ◽  
Follicular Epithelium ◽  
Oocyte Nucleus ◽  
Cortical Region ◽  
Extracellular Matrix Components

In Drosophila dorsoventral (DV) polarity arises during oogenesis when the oocyte nucleus moves from a central posterior to an asymmetrical anterior position. Nuclear movement is a symmetry–breaking step and establishes orthogonality between the anteroposterior and the DV axes. The asymmetrically anchored nucleus defines a cortical region within the oocyte which accumulates high levels of gurken messenger RNA (mRNA) and protein. Gurken is an ovarian–specific member of the transforming growth factor–α (TGF–α) family of secreted ligands. Secreted Gurken forms a concentration gradient that results in a dorsal–to–ventral gradient of EGF receptor activation in the follicle cells surrounding the oocyte. This leads to concentration–dependent activation or repression of target genes of the EGF pathway in the follicular epithelium. One outcome of this process is the restriction of pipe expression to a ventral domain that comprises 40% of the egg circumference. Pipe presumably modifies extracellular matrix components that are secreted by the follicle cells and are present at the ventral side of embryo after egg deposition. Here, they activate a proteolytic cascade that generates a gradient of the diffusible ligand, Spätzle. Spätzle activates the Toll receptor at the surface of the embryo that stimulates the nuclear uptake of the transcription factor Dorsal. This leads to a nuclear concentration gradient of Dorsal that specifies the cell types along the DV axis of the embryo.

Combined activities of Gurken and decapentaplegic specify dorsal chorion structures of the Drosophila egg

Development ◽  
2000 ◽  
Vol 127 (4) ◽  
pp. 841-850 ◽  
Author(s):  
F. Peri ◽  
S. Roth
Keyword(s):  
Egf Receptor ◽  
Receptor Activation ◽  
Posterior Pole ◽  
Follicle Cells ◽  
Follicular Epithelium ◽  
Oocyte Nucleus ◽  
Main Body ◽  
Dorsal Appendage ◽  
Broad Complex ◽  
Anterior Posterior

During Drosophila oogenesis Gurken, associated with the oocyte nucleus, activates the Drosophila EGF receptor in the follicular epithelium. Gurken first specifies posterior follicle cells, which in turn signal back to the oocyte to induce the migration of the oocyte nucleus from a posterior to an anterior-dorsal position. Here, Gurken signals again to specify dorsal follicle cells, which give rise to dorsal chorion structures including the dorsal appendages. If Gurken signaling is delayed and starts after stage 6 of oogenesis the nucleus remains at the posterior pole of the oocyte. Eggs develop with a posterior ring of dorsal appendage material that is produced by main-body follicle cells expressing the gene Broad-Complex. They encircle terminal follicle cells expressing variable amounts of the TGFbeta homologue, decapentaplegic. By ectopically expressing decapentaplegic and clonal analysis with Mothers against dpp we show that Decapentaplegic signaling is required for Broad-Complex expression. Thus, the specification and positioning of dorsal appendages along the anterior-posterior axis depends on the intersection of both Gurken and Decapentaplegic signaling. This intersection also induces rhomboid expression and thereby initiates the positive feedback loop of EGF receptor activation, which positions the dorsal appendages along the dorsal-ventral egg axis.

TGF-β1-induced EMT can occur independently of its proapoptotic effects and is aided by EGF receptor activation

2006 ◽  
Vol 290 (5) ◽  
pp. F1202-F1212 ◽  
Author(s):  
Neil G. Docherty ◽  
Orfhlaith E. O'Sullivan ◽  
Declan A. Healy ◽  
Madeline Murphy ◽  
Amanda J. O'Neill ◽  
...  
Keyword(s):  
Growth Factor ◽  
Western Blotting ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Receptor Activation ◽  
Concomitant Treatment ◽  
Dependent Manner ◽  
Akt Phosphorylation

Apoptosis and epithelial-mesenchymal transdifferentiation (EMT) occur in stressed tubular epithelial cells and contribute to renal fibrosis. Transforming growth factor (TGF)-β1 promotes these responses and we examined whether the processes were interdependent in vitro. Direct (caspase inhibition) and indirect [epidermal growth factor (EGF) receptor stimulation] strategies were used to block apoptosis during TGF-β1 stimulation, and the subsequent effect on EMT was assessed. HK-2 cells were exposed to TGF-β1 with or without preincubation with ZVAD-FMK (pan-caspase inhibitor) or concomitant treatment with EGF plus or minus preincubation with LY-294002 (PI3-kinase inhibitor). Cells were then assessed for apoptosis and proliferation by flow cytometry, crystal violet assay, and Western blotting. Markers of EMT were assessed by microscopy, immunofluorescence, real-time RT-PCR, Western blotting, PAI-1 reporter assay, and collagen gel contraction assay. TGF-β1 caused apoptosis and priming for staurosporine-induced apoptosis. This was blocked by ZVAD-FMK. However, ZVAD-FMK did not prevent EMT following TGF-β1 treatment. EGF inhibited apoptosis and facilitated TGF-β1 induction of EMT by increasing proliferation and accentuating E-cadherin loss. Additionally, EGF significantly enhanced TGF-β1-induced collagen I gel contraction. EGF increased Akt phosphorylation during EMT, and the prosurvival effect of this was confirmed using LY-294002, which reduced EGF-induced Akt phosphorylation and reversed its antiapoptotic and proproliferatory effects. TGF-β1 induces EMT independently of its proapoptotic effects. TGF-β1 and EGF together lead to EMT. EGF increases proliferation and resistance to apoptosis during EMT in a PI3-K Akt-dependent manner. In vivo, EGF receptor activation may assist in the selective survival of a transdifferentiated, profibrotic cell type.

Two signalling pathways specify localised expression of the Broad-Complex in Drosophila eggshell patterning and morphogenesis

Development ◽  
1997 ◽  
Vol 124 (22) ◽  
pp. 4639-4647 ◽  
Author(s):  
W.M. Deng ◽  
M. Bownes
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Signalling Pathway ◽  
Follicle Cells ◽  
Signalling Pathways ◽  
Gene Encoding ◽  
Broad Complex

The Drosophila eggshell, which has a pair of chorionic appendages (dorsal appendages) located asymmetrically along both the anterior/posterior and dorsal/ventral axes, provides a good model to study signal instructed morphogenesis. We show that the Broad-Complex, a gene encoding zinc-finger transcription factors, is essential for the morphogenesis of dorsal appendages and is expressed in a bilaterally symmetrical pattern in the lateral-dorsal-anterior follicle cells during late oogenesis. This is induced and specified along the dorsoventral axis by an epidermal growth factor receptor signalling pathway, which includes a localised transforming growth factor-alpha like molecule, Gurken, in the oocyte and the Drosophila EGF receptor homologue, Torpedo, in the surrounding somatic follicle cells. Furthermore, the precisely localised expression of BR-C along the AP axis requires a separate signalling pathway, initiated by a transforming growth factor-beta homologue, Decapentaplegic, in nearby follicle cells. These two signalling pathways, one from the oocyte and the other from the follicle cells, co-ordinately specify patches of follicle cells to express the Broad-Complex in a unique position in respect to both major axes, which in turn directs the differentiation of the dorsal appendages in the correct position on the eggshell.

scholarly journals TGF alpha can act as a chemoattractant to perioptic mesenchymal cells in developing mouse eyes

Development ◽  
1995 ◽  
Vol 121 (6) ◽  
pp. 1669-1680 ◽  
Author(s):  
L.W. Reneker ◽  
D.W. Silversides ◽  
K. Patel ◽  
P.A. Overbeek
Keyword(s):  
Growth Factor ◽  
Transgenic Mice ◽  
Cell Fate ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Eye Development ◽  
Biological Activities ◽  
Receptor Activation ◽  
Mesenchymal Cells ◽  
Migratory Response

Growth factors are believed to play an important role in regulating cell fate and cell behavior during embryonic development. Transforming growth factor alpha (TGF alpha), a member of the epidermal growth factor (EGF) superfamily, is a small polypeptide growth factor. Upon binding to its receptor, the EGF receptor (EGFR), TGF alpha can exert diverse biological activities, such as induction of cell proliferation or differentiation. To explore the possibility that TGF alpha might regulate cell fate during murine eye development, we generated transgenic mice that express human TGF alpha in the lens under the control of the mouse alpha A-crystallin promoter. The transgenic mice displayed multiple eye defects, including corneal opacities, cataracts and microphthalmia. At early embryonic stages TGF alpha induced the perioptic mesenchymal cells to migrate abnormally into the eye and accumulate around the lens. In situ hybridization revealed that the EGFR mRNA is highly expressed in the perioptic mesenchyme, suggesting that the migratory response is mediated by receptor activation. In order to test this model, the TGF alpha transgenic mice were bred to EGFR mutant waved-2 (wa-2) mice. We found that the eye defects of the TGF alpha transgenic mice are significantly abated in the wa-2 homozygote background. Because the EGFR mutation in the wa-2 mice is located in the receptor kinase domain, this result indicates that the receptor tyrosine kinase activity is critical for signaling the migratory response. Taken together, our studies demonstrate that TGF alpha is capable of altering the migratory decisions and behavior of perioptic mesenchyme during eye development.

scholarly journals EGF and amphiregulin differentially regulate Cbl recruitment to endosomes and EGF receptor fate

2008 ◽  
Vol 410 (3) ◽  
pp. 585-594 ◽  
Author(s):  
Kathryn A. Stern ◽  
Trenton L. Place ◽  
Nancy L. Lill
Keyword(s):  
Growth Factor ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Partial Agonist ◽  
Ectopic Expression ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Transforming Growth Factor Α ◽  
Molecular Events ◽  
Factor Α

EGF-R [EGF (epidermal growth factor) receptor] ligands can promote or inhibit cell growth. The biological outcome of receptor activation is dictated, at least in part, by ligand-specified patterns of endocytic trafficking. EGF-R trafficking downstream of the ligands EGF and TGF-α (transforming growth factor-α) has been investigated extensively. However, less is known about EGF-R fates induced by the ligands BTC (betacellulin) and AR (amphiregulin). We undertook comparative analyses to identify ligand-specific molecular events that regulate EGF-R trafficking and degradation. EGF (17 nM) and BTC (8.5 nM) induced significant EGF-R degradation, with or without ectopic expression of the ubiquitin ligase Cbl. Human recombinant AR (17 nM) failed to affect receptor degradation in either case. Notably, levels of ligand-induced EGF-R ubiquitination did not correlate strictly with receptor degradation. Dose–response experiments revealed that AR at a saturating concentration was a partial agonist at the EGF-R, with approx. 40% efficacy (relative to EGF) at inducing receptor tyrosine phosphorylation, ubiquitination and association with Cbl. EGF-R down-regulation and degradation also were compromised upon cell stimulation with AR (136 nM). These outcomes correlated with decreased degradation of the Cbl substrate and internalization inhibitor hSprouty2. Downstream of the hSprouty2 checkpoint in AR-stimulated cells, Cbl-free EGF-R was incorporated into endosomes from which Cbl–EGF-R complexes were excluded. Our results suggest that the AR-specific EGF-R fate results from decreased hSprouty2 degradation and reduced Cbl recruitment to underphosphorylated EGF-R, two effects that impair EGF-R trafficking to lysosomes.

scholarly journals The Tetraspanin Cd9 Associates with Transmembrane TGF-α and Regulates TGF-α–Induced Egf Receptor Activation and Cell Proliferation

2000 ◽  
Vol 148 (3) ◽  
pp. 591-602 ◽  
Author(s):  
Wen Shi ◽  
Huizhou Fan ◽  
Lillian Shum ◽  
Rik Derynck
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Receptor Activation ◽  
Tyrosine Kinase Receptor ◽  
Transforming Growth Factor Α ◽  
Egfr Activation ◽  
Membrane Spanning ◽  
Factor Α

Transforming growth factor-α (TGF-α) is a member of the EGF growth factor family. Both transmembrane TGF-α and the proteolytically released soluble TGF-α can bind to the EGF/TGF-α tyrosine kinase receptor (EGFR) and activate the EGFR-induced signaling pathways. We now demonstrate that transmembrane TGF-α physically interacts with CD9, a protein with four membrane spanning domains that is frequently coexpressed with TGF-α in carcinomas. This interaction was mediated through the extracellular domain of transmembrane TGF-α. CD9 expression strongly decreased the growth factor– and PMA- induced proteolytic conversions of transmembrane to soluble TGF-α and strongly enhanced the TGF- α–induced EGFR activation, presumably in conjunction with increased expression of transmembrane TGF-α. In juxtacrine assays, the CD9-induced EGFR hyperactivation by transmembrane TGF-α resulted in increased proliferation. In contrast, CD9 coexpression with transmembrane TGF-α decreased the autocrine growth stimulatory effect of TGF-α in epithelial cells. This decrease was associated with increased expression of the cdk inhibitor, p21CIP1. These data reveal that the association of CD9 with transmembrane TGF-α regulates ligand-induced activation of the EGFR, and results in altered cell proliferation.

scholarly journals mago nashi mediates the posterior follicle cell-to-oocyte signal to organize axis formation in Drosophila

Development ◽  
1997 ◽  
Vol 124 (16) ◽  
pp. 3197-3207 ◽  
Author(s):  
P.A. Newmark ◽  
S.E. Mohr ◽  
L. Gong ◽  
R.E. Boswell
Keyword(s):  
Germ Plasm ◽  
Egf Receptor ◽  
Germ Line ◽  
Follicle Cell ◽  
Posterior Pole ◽  
Follicle Cells ◽  
Oocyte Nucleus ◽  
Axis Formation ◽  
Pole Plasm ◽  
Mago Nashi

Establishment of the anteroposterior and dorsoventral axes in the Drosophila egg chamber requires reciprocal signaling between the germ line and soma. Upon activation of the Drosophila EGF receptor in the posterior follicle cells, these cells signal back to the oocyte, resulting in a reorganization of the oocyte cytoplasm and anterodorsal migration of the oocyte nucleus. We demonstrate that the gene mago nashi (mago) encodes an evolutionarily conserved protein that must be localized within the posterior pole plasm for germ-plasm assembly and Caenorhabditis elegans mago is a functional homologue of Drosophila mago. In the absence of mago+ function during oogenesis, the anteroposterior and dorsoventral coordinates of the oocyte are not specified and the germ plasm fails to assemble.

Mechanism of activation of theDrosophilaEGF Receptor by the TGFα ligand Gurken during oogenesis

Development ◽  
2002 ◽  
Vol 129 (1) ◽  
pp. 175-186 ◽  
Author(s):  
Christian Ghiglione ◽  
Erika A. Bach ◽  
Yolande Paraiso ◽  
Kermit L. Carraway ◽  
Stéphane Noselli ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Follicle Cells ◽  
Follicular Epithelium ◽  
Soluble Form ◽  
Culture Cells ◽  
Epidermal Growth ◽  
Membrane Bound

We have analyzed the mechanism of activation of the Epidermal growth factor receptor (Egfr) by the transforming growth factor (TGF) α-like molecule, Gurken (Grk). Grk is expressed in the oocyte and activates the Egfr in the surrounding follicle cells during oogenesis. We show that expression of either a membrane bound form of Grk (mbGrk), or a secreted form of Grk (secGrk), in either the follicle cells or in the germline, activates the Egfr. In tissue culture cells, both forms can bind to the Egfr; however, only the soluble form can trigger Egfr signaling, which is consistent with the observed cleavage of Grk in vivo. We find that the two transmembrane proteins Star and Brho potentiate the activity of mbGrk. These two proteins collaborate to promote an activating proteolytic cleavage and release of Grk. After cleavage, the extracellular domain of Grk is secreted from the oocyte to activate the Egfr in the follicular epithelium.

Mechanisms of Gurken-dependentpiperegulation and the robustness of dorsoventral patterning inDrosophila

Development ◽  
2002 ◽  
Vol 129 (12) ◽  
pp. 2965-2975 ◽  
Author(s):  
Francesca Peri ◽  
Martin Technau ◽  
Siegfried Roth
Keyword(s):  
Egf Receptor ◽  
Follicle Cell ◽  
Dorsal Side ◽  
Drosophila Embryo ◽  
Follicle Cells ◽  
Follicular Epithelium ◽  
Axis Formation ◽  
Embryonic Patterning ◽  
Cell Fates ◽  
Egg Chamber

The restriction of Pipe, a potential glycosaminoglycan-modifying enzyme, to ventral follicle cells of the egg chamber is essential for dorsoventral axis formation in the Drosophila embryo. pipe repression depends on the TGFα-like ligand Gurken, which activates the Drosophila EGF receptor in dorsal follicle cells. An analysis of Raf mutant clones shows that EGF signalling is required cell-autonomously in all dorsal follicle cells along the anteroposterior axis of the egg chamber to repress pipe. However, the autoactivation of EGF signalling important for dorsal follicle cell patterning has no influence on pipe expression. Clonal analysis shows that also the mirror-fringe cassette suggested to establish a secondary signalling centre in the follicular epithelium is not involved in pipe regulation. These findings support the view that the pipe domain is directly delimited by a long-range Gurken gradient. Pipe induces ventral cell fates in the embryo via activation of the Spätzle/Toll pathway. However, large dorsal patches of ectopic pipe expression induced by Raf clones rarely affect embryonic patterning if they are separated from the endogenous pipe domain. This indicates that potent inhibitory processes prevent pipe dependent Toll activation at the dorsal side of the egg.

scholarly journals The Blockade of TACE-Dependent EGF Receptor Activation by Losartan-Erlotinib Combination Attenuates Renal Fibrosis Formation in 5/6-Nephrectomized Rats Under Vitamin D Deficiency

2021 ◽  
Vol 7 ◽  
Author(s):  
Janaína Garcia Gonçalves ◽  
Daniele Canale ◽  
Ana Carolina de Bragança ◽  
Antonio Carlos Seguro ◽  
Maria Heloisa Massola Shimizu ◽  
...  
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Vitamin D Deficiency ◽  
Renal Fibrosis ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Alternative Pathway ◽  
Receptor Activation ◽  
Public Health Issue ◽  
Ckd Progression

Chronic kidney disease (CKD) has been considered a major public health issue. In addition to cardiovascular diseases and infections, hypovitaminosis D has been considered a non-traditional aggravating factor for CKD progression. Interstitial fibrosis is a hallmark of CKD strongly correlated with deterioration of renal function. Transforming growth factor β (TGF-β) is the major regulatory profibrotic cytokine in CKD. Many injurious stimuli converge on the TGF-β pathway, which has context-dependent pleiotropic effects and interacts with several related renal fibrosis formation (RFF) pathways. Epidermal growth factor receptor (EGFR) is critically involved in CKD progression, exerting a pathogenic role in RFF associated with TGF-β-related fibrogenesis. Among others, EGFR pathway can be activated by a disintegrin and a metalloproteinase known as tumor necrosis factor α-converting enzyme (TACE). Currently no effective therapy is available to completely arrest RFF and slow the progression of CKD. Therefore, we investigated the effects of a double treatment with losartan potassium (L), an AT1R antagonist, and the tyrosine kinase inhibitor erlotinib (E) on the alternative pathway of RFF related to TACE-dependent EGFR activation in 5/6-nephrectomized rats under vitamin D deficiency (D). During the 90-day protocol, male Wistar rats under D, were submitted to 5/6 nephrectomy (N) on day 30 and randomized into four groups: N+D, no treatment; N+D+L, received losartan (50 mg/kg/day); N+D+E, received erlotinib (6 mg/kg/day); N+D+L+E received losartan+erlotinib treatment. N+D+L+E data demonstrated that the double treatment with losartan+erlotinib not only blocked the TACE-dependent EGF receptor activation but also prevented the expression of TGF-β, protecting against RFF. This renoprotection by losartan+erlotinib was corroborated by a lower expression of ECM proteins and markers of phenotypic alteration as well as a lesser inflammatory cell infiltrate. Although erlotinib alone has been emerging as a renoprotective drug, its association with losartan should be considered as a potential therapeutic strategy on the modulation of RFF.

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