Molecular cloning of Notch, a locus affecting neurogenesis in Drosophila melanogaster.

Artavanis‐Tsakonas, Spyros; Muskavitch, Marc A. T.; Yedvobnick, Barry

doi:10.1073/pnas.80.7.1977

Cited by 173 publications

(99 citation statements)

References 18 publications

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“…Notch-1 is a known early factor important in cell fate decisions, boundary development, epithelial to mesenchymal transition (EMT) cell shape changes, and has been implicated with heart valve development at later stages (Artavanis-Tsakonis et al, 1983;Conlon et al, 1995;Micchelli and Blair, 1999;McLaughlin et al, 2000;Rones et al, 2000;Taichman et al, 2002;Kikuchi et al, 2004;Timmerman et al, 2004). EMT transition or the converse, mesenchymal to epithelial transformation, is an important step in cardiac organogenesis (Linask, 1992a,b).…”

Section: Notch-1 Modulationmentioning

confidence: 99%

Early temporal‐specific responses and differential sensitivity to lithium and Wnt‐3A exposure during heart development

Manisastry

Han

Linask

2006

Developmental Dynamics

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Members of both Wnt and bone morphogenetic protein (BMP) families of signaling molecules are important in heart development. We previously demonstrated that ␤-catenin, a key downstream intermediary of the canonical Wnt signaling pathway, delineates the dorsal boundary of the cardiac compartments in an anteroposterior progression. We hypothesized the progression involves canonical Wnt signaling and reflects development of the primary body axis of the embryo. A similar anteroposterior signaling wave leading to cardiac cell specification involves inductive signaling by BMP-2 synthesized by the underlying endoderm in anterior bilateral regions. Any molecule that disrupts the normal balance of Wnt and BMP concentrations within the heart field may be expected to affect early heart development. The canonical Wnt signaling step mimicked by lithium involves inactivation of glycogen synthase kinase-3␤ (GSK-3␤; Klein and Melton [1996] Proc. Natl. Acad. Sci. U. S. A. 93:8455-8459). We show that lithium, Wnt-3A, and an inhibitor of GSK-3␤, SB415286, affect early heart development at the cardiac specification stages. We demonstrate that normal expression patterns of key signaling molecules as Notch-1 and Dkk-1 are altered in the anterior mesoderm within the heart fields by a one-time exposure to lithium, or by noggin inhibition of BMP, at Hamburger and Hamilton (HH) stage 3 during chick embryonic development. The severity of developmental defects is greatest with exposure to lithium or Wnt-3A at HH stage 3 and decreases at HH stage 4. Taken together, our results demonstrate that there are temporal-specific responses and differential sensitivities to lithium/Wnt-3A exposure during early heart development.

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Section: Notch-1 Modulationmentioning

confidence: 99%

Early temporal‐specific responses and differential sensitivity to lithium and Wnt‐3A exposure during heart development

Manisastry

Han

Linask

2006

Developmental Dynamics

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“…7C), the level of Notch expressed from the Notch gt-FH transgene should be similar to that expressed from an endogenous copy of Notch. Drosophila Notch resides on the X chromosome, and males harboring a null allele of Notch are embryonic lethal (47). However, one copy of Notch gt-FH rescued the lethality of Notch-null males.…”

Section: Gt-fhmentioning

confidence: 99%

Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch

Harvey

Rana

Moss

et al. 2016

Journal of Biological Chemistry

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Glycosylation of the Notch receptor is essential for its activity and serves as an important modulator of signaling. Three major forms of O-glycosylation are predicted to occur at consensus sites within the epidermal growth factor-like repeats in the extracellular domain of the receptor: O-fucosylation, O-glucosylation, and O-GlcNAcylation. We have performed comprehensive mass spectral analyses of these three types of O-glycosylation on Drosophila Notch produced in S2 cells and identified peptides containing all 22 predicted O-fucose sites, all 18 predicted O-glucose sites, and all 18 putative O-GlcNAc sites. Using semiquantitative mass spectral methods, we have evaluated the occupancy and relative amounts of glycans at each site. The majority of the O-fucose sites were modified to high stoichiometries. Upon expression of the ␤3-N-acetylglucosaminyltransferase Fringe with Notch, we observed varying degrees of elongation beyond O-fucose monosaccharide, indicating that Fringe preferentially modifies certain sites more than others. Rumi modified O-glucose sites to high stoichiometries, although elongation of the O-glucose was site-specific. Although the current putative consensus sequence for O-GlcNAcylation predicts 18 O-GlcNAc sites on Notch, we only observed apparent O-GlcNAc modification at five sites. In addition, we performed mass spectral analysis on endogenous Notch purified from Drosophila embryos and found that the glycosylation states were similar to those found on Notch from S2 cells. These data provide foundational information for future studies investigating the mechanisms of how O-glycosylation regulates Notch activity.

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“…This possibility arises from several reports that overexpression of Notch ligand can induce regulatory cells (13)(14)(15); in addition, it has recently been shown that Tregs with membrane-bound TGF-␤ stimulate the Notch pathway and that such stimulation is necessary for the induction of tolerance to respiratory Ags in the airway (16). Notch is a phylogenetically old molecule that was first identified as a signaling component essential for the differentiation of the embryonic nervous system of Drosophila (17,18). Later studies showed that Notch was also involved in mammalian differentiation processes including those governing the development of the immune system (19).…”

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confidence: 99%

Notch1 Signaling and Regulatory T Cell Function

Asano

Watanabe

Kitani

et al. 2008

The Journal of Immunology

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Previous studies have shown that the Notch1 and TGF-β signaling pathways are mutually re-enforcing. Given recent evidence that regulatory T cell (Treg) effector function is mediated by TGF-β signaling, we investigated whether Notch1 signaling also participated in Treg effector function. Initial studies showed that Notch1 ligands, particularly Jagged1, are present on Tregs and that, indeed, blockade of Notch1 signaling with an anti-Jagged1 or a blocking anti-Notch1 Ab inhibits Treg suppressor function in vitro. We then showed that a signaling component generated by Notch1 activation (Notch1 intracellular domain) of dendritic cells physically interacts with a signaling component generated by TGF-β signaling (pSmad3). Furthermore, this interaction has functional downstream effects because over-expression of Notch1 intracellular domain facilitates pSmad3 translocation to the nucleus and enhances pSmad3 transcriptional activity of a Smad-sensitive promoter linked to a luciferase reporter. Finally, we showed that blockade of TGF-β signaling and Notch signaling did not have additive inhibitory effects on Treg suppressor function. These results are consistent with the conclusion that Notch1 signaling facilitates TGF-β-mediated effector function of Tregs.

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Molecular cloning of Notch, a locus affecting neurogenesis in Drosophila melanogaster.

Cited by 173 publications

References 18 publications

Early temporal‐specific responses and differential sensitivity to lithium and Wnt‐3A exposure during heart development

Early temporal‐specific responses and differential sensitivity to lithium and Wnt‐3A exposure during heart development

Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch

Notch1 Signaling and Regulatory T Cell Function

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