Interactions among Delta, Serrate and Fringe modulate Notch activity during Drosophila wing development

Development ◽  
1998 ◽  
Vol 125 (15) ◽  
pp. 2951-2962 ◽  
Author(s):  
T. Klein ◽  
A.M. Arias
Keyword(s):  
Notch Signalling ◽  
Dominant Negative ◽  
Wing Development ◽  
Notch Signalling Pathway ◽  
Notch Ligand ◽  
Drosophila Wing ◽  
Signalling Molecule ◽  
Dorsoventral Boundary ◽  
Notch Ligands ◽  
Specific Nuclear Protein

The Notch signalling pathway plays an important role during the development of the wing primordium, especially of the wing blade and margin. In these processes, the activity of Notch is controlled by the activity of the dorsal specific nuclear protein Apterous, which regulates the expression of the Notch ligand, Serrate, and the Fringe signalling molecule. The other Notch ligand, Delta, also plays a role in the development and patterning of the wing. It has been proposed that Fringe modulates the ability of Serrate and Delta to signal through Notch and thereby restricts Notch signalling to the dorsoventral boundary of the developing wing blade. Here we report the results of experiments aimed at establishing the relationships between Fringe, Serrate and Delta during wing development. We find that Serrate is not required for the initiation of wing development but rather for the expansion and early patterning of the wing primordium. We provide evidence that, at the onset of wing development, Delta is under the control of apterous and might be the Notch ligand in this process. In addition, we find that Fringe function requires Su(H). Our results suggest that Notch signalling during wing development relies on careful balances between positive and dominant negative interactions between Notch ligands, some of which are mediated by Fringe.

Expression and function of decapentaplegic and thick veins during the differentiation of the veins in the Drosophila wing

Development ◽  
1997 ◽  
Vol 124 (5) ◽  
pp. 1007-1018 ◽  
Author(s):  
J.F. Celis de
Keyword(s):  
Imaginal Disc ◽  
Signal Transduction Pathways ◽  
Pupal Development ◽  
Transmembrane Receptors ◽  
Notch Ligand ◽  
Regulatory Interactions ◽  
Drosophila Wing ◽  
Signalling Molecule ◽  
And Function

The differentiation of the veins in the Drosophila wing involves the coordinate activities of several signal transduction pathways, including those mediated by the transmembrane receptors Torpedo and Notch. In this report, the role of the signalling molecule Decapentaplegic during vein differentiation has been analysed. It is shown that decapentaplegic is expressed in the pupal veins under the control of genes that establish vein territories in the imaginal disc. Decapentaplegic, acting through its receptor Thick veins, activates vein differentiation and restricts expression of both veinlet and the Notch-ligand Delta to the developing veins. Genetic combinations between mutations that increase or reduce Notch, veinlet and decapentaplegic activities suggest that the maintenance of the vein differentiation state during pupal development involves cross-regulatory interactions between these pathways.

Serrate-mediated activation of Notch is specifically blocked by the product of the gene fringe in the dorsal compartment of the Drosophila wing imaginal disc

Development ◽  
1997 ◽  
Vol 124 (15) ◽  
pp. 2973-2981 ◽  
Author(s):  
R.J. Fleming ◽  
Y. Gu ◽  
N.A. Hukriede
Keyword(s):  
Imaginal Disc ◽  
Ectopic Expression ◽  
Wing Disc ◽  
Specific Response ◽  
Wing Margin ◽  
Drosophila Wing ◽  
Imaginal Wing Disc ◽  
Dorsoventral Boundary ◽  
Drosophila Cells ◽  
Notch Ligands

In the developing imaginal wing disc of Drosophila, cells at the dorsoventral boundary require localized Notch activity for specification of the wing margin. The Notch ligands Serrate and Delta are required on opposite sides of the presumptive wing margin and, even though activated forms of Notch generate responses on both sides of the dorsoventral boundary, each ligand generates a compartment-specific response. In this report we demonstrate that Serrate, which is expressed in the dorsal compartment, does not signal in the dorsal regions due to the action of the fringe gene product. Using ectopic expression, we show that regulation of Serrate by fringe occurs at the level of protein and not Serrate transcription. Furthermore, replacement of the N-terminal region of Serrate with the corresponding region of Delta abolishes the ability of fringe to regulate Serrate without altering Serrate-specific signaling.

Feed-back mechanisms affecting Notch activation at the dorsoventral boundary in the Drosophila wing

Development ◽  
1997 ◽  
Vol 124 (17) ◽  
pp. 3241-3251 ◽  
Author(s):  
J.F. Celis de ◽  
S. Bray
Keyword(s):  
Positive Feedback ◽  
Target Genes ◽  
Normal Growth ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Drosophila Wing ◽  
Negative Effect ◽  
Dorsoventral Boundary ◽  
Late Stages ◽  
Notch Activation

Notch function is required at the dorsoventral boundary of the developing Drosophila wing for its normal growth and patterning. We find that clones of cells expressing either Notch or its ligands Delta and Serrate in the wing mimic Notch activation at the dorsoventral boundary producing non-autonomous effects on proliferation, and activating expression of the target genes E(spl), wingless and cut. The analysis of these clones reveals several mechanisms important for maintaining and delimiting Notch function at the dorsoventral boundary. First, Notch activation in the wing leads to increased production of Delta and Serrate generating a positive feedback loop that maintains signalling. We propose that during normal development, wingless co-operates with Notch to reinforce this positive feedback and Cut, which is activated by Notch at late stages, acts antagonistically to prevent Delta and Serrate expression. Second, high levels of Delta and Serrate have a dominant negative effect on Notch, so that at late stages Notch can only be activated in cells next to the ligand-producing cells. Thus the combined effects of Notch and its target genes cut and wingless regulate the expression of Notch ligands which restrict Notch activity to the dorsoventral boundary.

Notch functions in developmental and tumour angiogenesis by diverse mechanisms1

2014 ◽  
Vol 42 (6) ◽  
pp. 1563-1568 ◽  
Author(s):  
Thaned Kangsamaksin ◽  
Ian W. Tattersall ◽  
Jan Kitajewski
Keyword(s):  
Tumour Growth ◽  
Cell Types ◽  
Notch Signalling ◽  
Stalk Cell ◽  
Tumour Angiogenesis ◽  
Notch Signalling Pathway ◽  
Retinal Angiogenesis ◽  
Multiple Cell ◽  
Epidermal Growth ◽  
Notch Ligands

The Notch signalling pathway is a key regulator of developmental and tumour angiogenesis. Inhibition of Delta-like 4 (Dll4)-mediated Notch signalling results in hyper-sprouting, demonstrating that Notch regulates tip-stalk cell identity in developing tissues and tumours. Paradoxically, Dll4 blockade leads to reduced tumour growth because the newly growing vessels are poorly perfused. To explore the potential for targeting Notch, we developed Notch inhibitors, termed the Notch1 decoys. A Notch1 decoy variant containing all 36 epidermal growth factor (EGF)-like repeats of the extracellular domain of rat Notch1 has been shown to inhibit both Dll and Jagged class Notch ligands. Thus this Notch1 decoy functions differently than Dll4-specific blockade, although it has the potential to inhibit Dll4 activity. Expression of the Notch1 decoy in mice disrupted tumour angiogenesis and inhibited tumour growth. To understand the mechanism by which Notch blockade acts, it is important to note that Notch can function in multiple cell types that make up the vasculature, including endothelial cells and perivascular cells. We investigated Notch function in retinal microglia and determined how myeloid-expressed Notch can influence macrophages and angiogenesis. We found that myeloid-specific loss of Notch1 reduced microglia recruitment and led to improper microglia localization during retinal angiogenesis. Thus either pharmacological inhibition of Notch signalling or genetic deficiencies of Notch function in microglia leads to abnormal angiogenesis.

Relationships between extramacrochaetae and Notch signalling in Drosophila wing development

Development ◽  
2000 ◽  
Vol 127 (11) ◽  
pp. 2383-2393 ◽  
Author(s):  
A. Baonza ◽  
J.F. de Celis ◽  
A. Garcia-Bellido
Keyword(s):  
Cell Proliferation ◽  
Genetic Interaction ◽  
Wing Disc ◽  
Notch Signalling ◽  
Wing Development ◽  
Notch Activity ◽  
Drosophila Wing ◽  
Vein Formation ◽  
Gene Enhancer ◽  
Enhancer Of Split

The function of extramacrochaetae is required during the development of the Drosophila wing in processes such as cell proliferation and vein differentiation. extramacrochaetae encodes a transcription factor of the HLH family, but unlike other members of this family, Extramacrochaetae lacks the basic region that is involved in interaction with DNA. Some phenotypes caused by extramacrochaetae in the wing are similar to those observed when Notch signalling is compromised. Furthermore, maximal levels of extramacrochaetae expression in the wing disc are restricted to places where Notch activity is higher, suggesting that extramacrochaetae could mediate some aspects of Notch signalling during wing development. We have studied the relationships between extramacrochaetae and Notch in wing development, with emphasis on the processes of vein formation and cell proliferation. We observe strong genetic interaction between extramacrochaetae and different components of the Notch signalling pathway, suggesting a functional relationship between them. We show that the higher level of extramacrochaetae expression coincides with the domain of expression of Notch and its downstream gene Enhancer of split-m(beta). The expression of extramacrochaetae at the dorso/ventral boundary and in boundary cells between veins and interveins depends on Notch activity. We propose that at least during vein differentiation and wing margin formation, extramacrochaetae is regulated by Notch and collaborates with other Notch-downstream genes such as Enhancer of split-m(beta).

scholarly journals Drosophila Cyclin G Is a Regulator of the Notch Signalling Pathway during Wing Development

PLoS ONE ◽  
2016 ◽  
Vol 11 (3) ◽  
pp. e0151477 ◽  
Author(s):  
Anja C. Nagel ◽  
Jutta Szawinski ◽  
Mirjam Zimmermann ◽  
Anette Preiss
Keyword(s):  
Notch Signalling ◽  
Signalling Pathway ◽  
Wing Development ◽  
Notch Signalling Pathway ◽  
Cyclin G

Notch signalling regulates veinlet expression and establishes boundaries between veins and interveins in the Drosophila wing

Development ◽  
1997 ◽  
Vol 124 (10) ◽  
pp. 1919-1928 ◽  
Author(s):  
J.F. de Celis ◽  
S. Bray ◽  
A. Garcia-Bellido
Keyword(s):  
Positive Feedback ◽  
Notch Pathway ◽  
Notch Signalling ◽  
Notch Ligand ◽  
Asymmetrical Distribution ◽  
Drosophila Wing ◽  
Split Gene ◽  
Enhancer Of Split ◽  
Notch Activation ◽  
In Cells

The veins in the Drosophila wing have a characteristic width, which is regulated by the activity of the Notch pathway. The expression of the Notch-ligand Delta is restricted to the developing veins, and coincides with places where Notch transcription is lower. We find that this asymmetrical distribution of ligand and receptor leads to activation of Notch on both sides of each vein within a territory of Delta-expressing cells, and to the establishment of boundary cells that separate the vein from adjacent interveins. In these cells, the expression of the Enhancer of split gene m beta is activated and the transcription of the vein-promoting gene veinlet is repressed, thus restricting vein differentiation. We propose that the establishment of vein thickness utilises a combination of mechanisms that include: (1) independent regulation of Notch and Delta expression in intervein and vein territories, (2) Notch activation by Delta in cells where Notch and Delta expression overlaps, (3) positive feedback on Notch transcription in cells where Notch has been activated and (4) repression of veinlet transcription by E(spl)m beta and maintenance of Delta expression by veinlet/torpedo activity.

Cis-interactions between Delta and Notch modulate neurogenic signalling in Drosophila

Development ◽  
1998 ◽  
Vol 125 (22) ◽  
pp. 4531-4540 ◽  
Author(s):  
T.L. Jacobsen ◽  
K. Brennan ◽  
A.M. Arias ◽  
M.A. Muskavitch
Keyword(s):  
Ectopic Expression ◽  
Notch Signalling ◽  
Dominant Negative ◽  
Notch Signalling Pathway ◽  
Dominant Negative Form ◽  
A Cell ◽  
Developmental Contexts ◽  
Tormogen Cell ◽  
To Receive ◽  
Negative Form

We find that ectopic expression of Delta or Serrate in neurons within developing bristle organs is capable of non-autonomously inducing the transformation of the pre-trichogen cell into a tormogen cell in a wide variety of developmental contexts. The frequencies at which Delta can induce these transformations are dependent on the level of ectopic Delta expression and the levels of endogenous Notch signalling pathway components. The pre-trichogen cell becomes more responsive to Delta- or Serrate-mediated transformation when the level of endogenous Delta is reduced and less responsive when the dosage of endogenous Delta is increased, supporting the hypothesis that Delta interferes autonomously with the ability of a cell to receive either signal. We also find that a dominant-negative form of Notch, ECN, is capable of autonomously interfering with the ability of a cell to generate the Delta signal. When the region of Notch that mediates trans-interactions between Delta and the Notch extracellular domain is removed from ECN, the ability of Delta to signal is restored. Our findings imply that cell-autonomous interactions between Delta and Notch can affect the ability of a cell to generate and to transduce a Delta-mediated signal. Finally, we present evidence that the Fringe protein can interfere with Delta- and Serrate-mediated signalling within developing bristle organs, in contrast to previous reports of the converse effects of Fringe on Delta signalling in the developing wing.

The intracellular deletions of Delta and Serrate define dominant negative forms of the Drosophila Notch ligands

Development ◽  
1996 ◽  
Vol 122 (8) ◽  
pp. 2465-2474 ◽  
Author(s):  
X. Sun ◽  
S. Artavanis-Tsakonas
Keyword(s):  
Notch Pathway ◽  
Notch Signalling ◽  
Dominant Negative ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Wild Type ◽  
Mutant Forms ◽  
Intracellular Domains ◽  
Notch Ligands ◽  
Enhancer Of Split

We examined the function of the intracellular domains of the two known Drosophila Notch ligands, Delta and Serrate, by expressing wild-type and mutant forms in the developing Drosophila eye under the sevenless promoter. The expression of intracellularly truncated forms of either Delta (sev-DlTM) or Serrate (sev-SerTM) leads to extra photoreceptor phenotypes, similar to the eye phenotypes associated with loss-of-function mutations of either Notch or Delta. Consistent with the notion that the truncated ligands reduce. Notch signalling activity, the eye phenotypes of sev-DlTM and sev-SerTM are enhanced by loss-of-function mutations in the Notch pathway elements, Notch, Delta, mastermind, deltex and groucho, but are suppressed by a duplication of Delta or mutations in Hairless, a negative regulator of the pathway. These observations were extended to the molecular level by demonstrating that the expression of Enhancer of split m delta, a target of Notch signalling, is down-regulated by the truncated ligands highly expressed in neighbouring cells. We conclude that the truncated ligands act as antagonists of Notch signalling.

A dominant-negative form of Serrate acts as a general antagonist of Notch activation

Development ◽  
1997 ◽  
Vol 124 (17) ◽  
pp. 3427-3437 ◽  
Author(s):  
N.A. Hukriede ◽  
Y. Gu ◽  
R.J. Fleming
Keyword(s):  
Wing Disc ◽  
Dominant Negative ◽  
Protein Domain ◽  
Truncated Form ◽  
Drosophila Wing ◽  
Compartment Boundary ◽  
Dominant Negative Form ◽  
Notch Ligands ◽  
Notch Activation ◽  
Negative Form

Specification of the dorsal-ventral compartment boundary in the developing Drosophila wing disc requires activation of NOTCH from its dorsal ligand SERRATE and its ventral ligand DELTA. Both NOTCH ligands are required in this process and one cannot be substituted for the other. In the wing disc, expression of a dominant-negative, truncated form of SERRATE called BD(G), is capable of inhibiting NOTCH activation in the ventral but not the dorsal compartments. We demonstrate that BD(G) can act as a general antagonist of both SERRATE and DELTA mediated NOTCH interactions, however, BD(G) retains the SERRATE protein domain targeted by FRINGE, hence its antagonistic effects are restricted in the dorsal wing disc. Our findings suggest a model in which ligand binding to NOTCH is a necessary but insufficient step toward NOTCH activation.

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