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.

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.

scholarly journals Drosophila IMP regulates Kuzbanian to control the timing of Notch signalling in the follicle cells

2018 ◽  
Author(s):  
Weronika Fic ◽  
Celia Faria ◽  
Daniel St Johnston
Keyword(s):  
Rna Binding ◽  
Notch Pathway ◽  
Notch Signalling ◽  
Follicle Cells ◽  
Over Expression ◽  
Apical Domain ◽  
Late Endosomes ◽  
Notch Cleavage ◽  
Mirna Pathway ◽  
Notch Activation

AbstractThe timing of Drosophila egg chamber development is controlled by a germline Delta signal that activates Notch in the follicle cells to induce them to cease proliferation and differentiate. Here we report that follicle cells lacking the RNA-binding protein IMP go through one extra division due to a delay in the Delta-dependent S2 cleavage of Notch. The timing of Notch activation has previously been shown to be controlled by cis-inhibition by Delta in the follicle cells, which is relieved when the miRNA pathway represses Delta expression. imp mutants are epistatic to Delta mutants and give an additive phenotype with belle and dicer mutants, indicating that IMP functions independently of both cis-inhibition and the miRNA pathway. We find that the imp phenotype is rescued by over-expression of Kuzbanian, the metalloprotease that mediates the Notch S2 cleavage. Furthermore, Kuzbanian is not enriched at the apical membrane in imp mutants, accumulating instead in late endosomes. Thus, IMP regulates Notch signalling by controlling the localisation of Kuzbanian to the apical domain, where Notch cleavage occurs, revealing a novel regulatory step in the Notch pathway.SummaryIMP regulates Notch signalling in follicle cells by controlling Kuzbanian localisation to the apical domain, where Notch cleavage occurs, revealing a novel regulatory step in the Notch pathway.

A subset of notch functions during Drosophila eye development require Su(H) and the E(spl) gene complex

Development ◽  
1998 ◽  
Vol 125 (15) ◽  
pp. 2893-2900 ◽  
Author(s):  
P. Ligoxygakis ◽  
S.Y. Yu ◽  
C. Delidakis ◽  
N.E. Baker
Keyword(s):  
Cell Fate ◽  
Notch Pathway ◽  
Signal Transduction Pathway ◽  
Notch Signalling ◽  
Transduction Pathway ◽  
Notch Signalling Pathway ◽  
Bhlh Genes ◽  
Drosophila Eye ◽  
Enhancer Of Split ◽  
Signalling Process

The Notch signalling pathway is involved in many processes where cell fate is decided. Previous work showed that Notch is required at successive steps during R8 specification in the Drosophila eye. Initially, Notch enhances atonal expression and promotes atonal function. After atonal autoregulation has been established, Notch signalling represses atonal expression during lateral specification. In this paper we investigate which known components of the Notch pathway are involved in each signalling process. Using clonal analysis we show that a ligand of Notch, Delta, is required along with Notch for both proneural enhancement and lateral specification, while the downstream components Suppressor-of-Hairless and Enhancer-of-Split are involved only in lateral specification. Our data point to a distinct signal transduction pathway during proneural enhancement by Notch. Using misexpression experiments we also show that particular Enhancer-of-split bHLH genes can differ greatly in their contribution to lateral specification.

scholarly journals Optogenetic inhibition of Delta reveals digital Notch signaling output during tissue differentiation

2019 ◽  
Author(s):  
Ranjith Viswanathan ◽  
Aleksandar Necakov ◽  
Mateusz Trylinski ◽  
Rohit Krishnan Harish ◽  
Daniel Krueger ◽  
...  
Keyword(s):  
Cellular Response ◽  
Genome Engineering ◽  
Notch Pathway ◽  
Tissue Level ◽  
Notch Signalling ◽  
Tissue Differentiation ◽  
Type Locus ◽  
Spatio Temporal ◽  
Notch Activation

AbstractSpatio-temporal regulation of signalling pathways plays a key role in generating diverse responses during the development of multicellular organisms. The role of signal dynamics in transferring signalling information in vivo is incompletely understood. Here we employ genome engineering in Drosophila melanogaster to generate a functional optogenetic allele of the Notch ligand Delta (opto-Delta), which replaces both copies of the endogenous wild type locus. Using clonal analysis, we show that optogenetic activation blocks Notch activation through cis-inhibition in signal-receiving cells. Signal perturbation in combination with quantitative analysis of a live transcriptional reporter of Notch pathway activity reveals differential tissue- and cell-scale regulatory modes. While at the tissue-level the duration of Notch signalling determines the probability with which a cellular response will occur, in individual cells Notch activation acts through a switch-like mechanism. Thus, time confers regulatory properties to Notch signalling that exhibit integrative digital behaviours during tissue differentiation.

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.

Composite signalling from Serrate and Delta establishes leg segments in Drosophila through Notch

Development ◽  
1999 ◽  
Vol 126 (13) ◽  
pp. 2993-3003 ◽  
Author(s):  
S.A. Bishop ◽  
T. Klein ◽  
A.M. Arias ◽  
J.P. Couso
Keyword(s):  
Gene Expression ◽  
Notch Signalling ◽  
Receptor Protein ◽  
General Mechanism ◽  
Developmental Processes ◽  
Downstream Gene Expression ◽  
Enhancer Of Split ◽  
Notch Activation

The receptor protein NOTCH and its ligands SERRATE and DELTA are involved in many developmental processes in invertebrates and vertebrates alike. Here we show that the expression of the Serrate and Delta genes patterns the segments of the leg in Drosophila by a combination of their signalling activities. Coincident stripes of Serrate and Delta expressing cells activate Enhancer of split expression in adjacent cells through Notch signalling. These cells form a patterning boundary from which a putative secondary signal leads to the development of leg joints. Elsewhere in the tarsal segments, signalling by DELTA and NOTCH is necessary for the development of non-joint parts of the leg. We propose that these two effects result from different thresholds of NOTCH activation, which are translated into different downstream gene expression effects. We propose a general mechanism for creation of boundaries by Notch signalling.

Notch signalling mediates segmentation of the Drosophila leg

Development ◽  
1998 ◽  
Vol 125 (23) ◽  
pp. 4617-4626 ◽  
Author(s):  
J.F. de Celis ◽  
D.M. Tyler ◽  
J. de Celis ◽  
S.J. Bray
Keyword(s):  
Gene Expression ◽  
Imaginal Disc ◽  
Flexible Structures ◽  
Notch Signalling ◽  
Pupal Development ◽  
Suppressor Of Hairless ◽  
Leg Development ◽  
Somite Formation ◽  
Enhancer Of Split ◽  
Notch Activation

The legs of Drosophila are divided into segments along the proximodistal axis by flexible structures called joints. The separation between segments is already visible in the imaginal disc as folds of the epithelium, and cells at segment boundaries have different morphology during pupal development. We find that Notch is locally activated in distal cells of each segment, as demonstrated by the restricted expression of the Enhancer of split mbeta gene, and is required for the formation of normal joints. The genes fringe, Delta, Serrate and Suppressor of Hairless, also participate in Notch function during leg development, and their expression is localised within the leg segments with respect to segment boundaries. The failure to form joints when Notch signalling is compromised leads to shortened legs, suggesting that the correct specification of segment boundaries is critical for normal leg growth. The requirement for Notch during leg development resembles that seen during somite formation in vertebrates and at the dorsal ventral boundary of the wing, suggesting that the creation of boundaries of gene expression through Notch activation plays a conserved role in co-ordinating growth and patterning.

scholarly journals NOTCH activity differentially affects alternative cell fate acquisition and maintenance

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Leonard Cheung ◽  
Paul Le Tissier ◽  
Sam GJ Goldsmith ◽  
Mathias Treier ◽  
Robin Lovell-Badge ◽  
...  
Keyword(s):  
Cell Fate ◽  
Notch Pathway ◽  
Notch Signalling ◽  
Differential Sensitivity ◽  
Endocrine Gland ◽  
Direct Role ◽  
Cell Lineages ◽  
Pituitary Development ◽  
Multiple Processes ◽  
Notch Activation

The pituitary is an essential endocrine gland regulating multiple processes. Regeneration of endocrine cells is of therapeutic interest and recent studies are promising, but mechanisms of endocrine cell fate acquisition need to be better characterised. The NOTCH pathway is important during pituitary development. Here, we further characterise its role in the murine pituitary, revealing differential sensitivity within and between lineages. In progenitors, NOTCH activation blocks cell fate acquisition, with time-dependant modulation. In differentiating cells, response to activation is blunted in the POU1F1 lineage, with apparently normal cell fate specification, while POMC cells remain sensitive. Absence of apparent defects in Pou1f1-Cre; Rbpjfl/fl mice further suggests no direct role for NOTCH signalling in POU1F1 cell fate acquisition. In contrast, in the POMC lineage, NICD expression induces a regression towards a progenitor-like state, suggesting that the NOTCH pathway specifically blocks POMC cell differentiation. These results have implications for pituitary development, plasticity and regeneration. Activation of NOTCH signalling in different cell lineages of the embryonic murine pituitary uncovers an unexpected differential sensitivity, and this consequently reveals new aspects of endocrine lineages development and plasticity.

scholarly journals 3375 Chronic inflammation promotes intestinal macrophages to become modulators of the Notch pathway

2019 ◽  
Vol 3 (s1) ◽  
pp. 4-5
Author(s):  
Eliseo Castillo
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Chronic Inflammation ◽  
Bacterial Translocation ◽  
Intestinal Inflammation ◽  
Notch Pathway ◽  
Goblet Cells ◽  
Chronic Colitis ◽  
Notch Ligand ◽  
Notch Activation

OBJECTIVES/SPECIFIC AIMS: The purpose of this research was to investigate how chronic inflammation promotes the generation of proinflammatory intestinal macrophages and if macrophages contribute to intestinal inflammation through Notch activation. METHODS/STUDY POPULATION: We utilized two animal models of chronic colitis, the chronic DSS-induced colitis mouse model and the spontaneous enterocolitis development in IL-10-deficient mice to investigate the role of chronic inflammation in the generation of proinflammatory intestinal macrophages and its influence in notch signaling. Bone marrow-derived monocytes were collected from each group and differentiated into macrophages (BMM) for gene and protein analysis. Ex vivo phenotypical and functional analysis of colonic macrophages was assessed as was the presence of goblet cells and mucosal T cells. In addition, we analyzed the development of goblet cell differentiation in colonoids in a co-culture system with proinflammatory macrophages. RESULTS/ANTICIPATED RESULTS: Our chronic inflammation models revealed an increase in proinflammatory macrophages present in the lamina propria and that these cells expressed significantly higher levels of notch ligand, Jagged1. Jagged 1 has been shown to enhance TH1 differentiation and T cells isolated from the mucosa of both chronic colitis models display strong TH1 skewing compared to controls. Chronic inflammation also contributes to intestinal barrier defects, enhanced permeability and bacterial translocation. We believe this enhanced intestinal permeability and subsequent bacterial translocation promote Jagged1 expression in intestinal macrophages. To support this concept, we show TLR stimulation induces the upregulation of Jagged1 in BMM. Additionally, the generation of BMM from our chronic DSS-induced colitis mice or age matched controls, revealed BMM derived from a host of chronic inflammation were skewed to a proinflammatory state prior to stimulation showing increased gene expression of several proinflammatory molecules including IL-1α, IL-1β, IL-12 and TNF-α. This would suggest monocytes migrating to the intestinal mucosa have more potential to become proinflammatory instead of traditional anti-inflammatory macrophages. Furthermore, proinflammatory notch ligand-positive macrophages co-cultured with colonoids, derived from unperturbed mice, significantly decreased the number of mucus producing goblet cells. In support of this observation, notch activation in intestinal stem cells promote absorptive (i.e. colonocytes) cell differentiation and prevents secretory cell (i.e. goblet cells) differentiation. DISCUSSION/SIGNIFICANCE OF IMPACT: Taken together, our results strongly suggest chronic inflammation modulates macrophages role in maintaining intestinal homeostasis through possible notch activation in both T cells and the intestinal epithelial barrier.

Functional relationships between Notch, Su(H) and the bHLH genes of the E(spl) complex: the E(spl) genes mediate only a subset of Notch activities during imaginal development

Development ◽  
1996 ◽  
Vol 122 (9) ◽  
pp. 2719-2728 ◽  
Author(s):  
J.F. de Celis ◽  
J. de Celis ◽  
P. Ligoxygakis ◽  
A. Preiss ◽  
C. Delidakis ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Ectopic Expression ◽  
Notch Pathway ◽  
Functional Relationships ◽  
Helix Loop Helix ◽  
Suppressor Of Hairless ◽  
Bhlh Genes ◽  
Enhancer Of Split ◽  
Notch Activation

The basic helix-loop-helix proteins of the Enhancer of split complex constitute a link between activation of the transmembrane receptor Notch and the resulting effects on transcription of downstream genes. The Suppressor of Hairless protein is the intermediary between Notch activation and expression of all Enhancer of split genes even though individual genes have distinct patterns of expression in imaginal discs. A comparison between the phenotypes produced by Notch, Suppressor of Hairless and Enhancer of split mutations in the wing and thorax indicate that Suppressor of Hairless and Notch requirements are indistinguishable, but that Enhancer of split activity is only essential for a subset of developmental processes involving Notch function. Likewise, the ectopic expression of Enhancer of split proteins does not reproduce all the consequences typical of ectopic Notch activation. We suggest that the Notch pathway bifurcates after the activation of Suppressor of Hairless and that Enhancer of split activity is not required when the consequence of Notch function is the transcriptional activation of downstream genes. Transcriptional activation mediated by Suppressor of Hairless and transcriptional repression mediated by Enhancer of split could provide greater diversity in the response of individual genes to Notch activity.

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