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Journal ArticleDOI

Notch Signaling: Cell Fate Control and Signal Integration in Development

30 Apr 1999-Science (American Association for the Advancement of Science)-Vol. 284, Iss: 5415, pp 770-776
TL;DR: Notch signaling defines an evolutionarily ancient cell interaction mechanism, which plays a fundamental role in metazoan development, providing a general developmental tool to influence organ formation and morphogenesis.
Abstract: Notch signaling defines an evolutionarily ancient cell interaction mechanism, which plays a fundamental role in metazoan development. Signals exchanged between neighboring cells through the Notch receptor can amplify and consolidate molecular differences, which eventually dictate cell fates. Thus, Notch signals control how cells respond to intrinsic or extrinsic developmental cues that are necessary to unfold specific developmental programs. Notch activity affects the implementation of differentiation, proliferation, and apoptotic programs, providing a general developmental tool to influence organ formation and morphogenesis.
Citations
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Journal ArticleDOI
TL;DR: Evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the beta-amyloid precursor protein by the protease called gamma-secretase has spurred progress toward novel therapeutics and provided discrete biochemical targets for drug screening and development.
Abstract: Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

5,890 citations

Journal ArticleDOI
07 Jan 2000-Cell
TL;DR: The important findings in the history of signal transduction are adequately covered in many reviews, and I have therefore cited reviews that discuss the seminal papers.

2,491 citations

Journal ArticleDOI
TL;DR: Although the intracellular transduction of the Notch signal is remarkably simple, with no secondary messengers, this pathway functions in an enormous diversity of developmental processes and its dysfunction is implicated in many cancers.
Abstract: A small number of signalling pathways are used iteratively to regulate cell fates, cell proliferation and cell death in development. Notch is the receptor in one such pathway, and is unusual in that most of its ligands are also transmembrane proteins; therefore signalling is restricted to neighbouring cells. Although the intracellular transduction of the Notch signal is remarkably simple, with no secondary messengers, this pathway functions in an enormous diversity of developmental processes and its dysfunction is implicated in many cancers.

2,450 citations

Journal ArticleDOI
TL;DR: It is found that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer.

2,251 citations


Cites methods from "Notch Signaling: Cell Fate Control ..."

  • ...The Notch signaling pathway is involved in de-months, 80% of ducts were normal; this percentage determining cellular fate in the embryonic development of a varietycreased to 68% at 4–5 months (p .089, using Poisson regresof tissues (Artavanis-Tsakonas et al., 1999), as well as in thesion)....

    [...]

Journal ArticleDOI
25 Feb 2000-Science
TL;DR: Both intrinsic and extrinsic signals regulate stem cell fate and some of these signals have now been identified and can be exploited in the application of stem cells to tissue replacement therapy.
Abstract: Stem cells are currently in the news for two reasons: the successful cultivation of human embryonic stem cell lines and reports that adult stem cells can differentiate into developmentally unrelated cell types, such as nerve cells into blood cells Both intrinsic and extrinsic signals regulate stem cell fate and some of these signals have now been identified Certain aspects of the stem cell microenvironment, or niche, are conserved between tissues, and this can be exploited in the application of stem cells to tissue replacement therapy

1,798 citations

References
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Journal ArticleDOI
24 Oct 1996-Nature
TL;DR: The characterization of the human Notch3 gene, which was previously mapped to the CADASIL critical region, is reported, indicating that Notch 3 could be the defective protein in CADASil patients.
Abstract: Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.

1,917 citations

Journal ArticleDOI
28 May 1998-Nature
TL;DR: It is shown that signalling by a constitutively active membrane-bound Notch-1 protein requires the proteolytic release of the Notch intracellular domain (NICD), which interacts preferentially with CSL.
Abstract: Notch proteins are ligand-activated transmembrane receptors involved in cell-fate selection throughout development1,2,3. No known enzymatic activity is contained within Notch and the molecular mechanism by which it transduces signals across the cell membrane is poorly understood. In many instances, Notch activation results in transcriptional changes in the nucleus through an association with members of the CSL family of DNA-binding proteins (where CSL stands for CBF1, Su(H), Lag-1)1,2,3,4. As Notch is located in the plasma membrane and CSL is a nuclear protein, two models have been proposed to explain how they interact (Fig. 1) . The first suggests that the two interact transiently at the membrane1,5,6,7. The second postulates that Notch is cleaved by a protease, enabling the cleaved fragment to enter the nucleus6,8,9,10,11,12,13,14. Here we show that signalling by a constitutively active membrane-bound Notch-1 protein requires the proteolytic release of the Notch intracellular domain (NICD), which interacts preferentially with CSL. Very small amounts of NICD are active, explaining why it is hard to detect in the nucleus in vivo. We also show that it is ligand binding that induces release of NICD.

1,625 citations

Journal ArticleDOI
28 Sep 1995-Nature
TL;DR: It is shown that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-JK and act as transcriptional activators through theKBF2-binding sites of the HES-1 promoter and block MyoD-induced myogenesis5-7.
Abstract: Notch belongs to a family of transmembrane proteins that are widely conserved from flies to vertebrates and are thought to be involved in cell-fate decisions. In Drosophila, the Suppressor of hairless (Su(H)) gene and genes of the Enhancer of split (E(Spl)) complex, which encode proteins of the basic helix-loop-helix type have been implicated in the Notch signalling pathway. Mammalian homologues of E(Spl), such as the mouse Hairy enhancer of split (HES-1), have been isolated. Both HES-1 and the intracellular domain of murine Notch (mNotch) are able to block MyoD-induced myogenesis. Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-J kappa (refs 8,9) and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter.

1,421 citations

Journal Article
01 Jan 1995-Science
TL;DR: The Notch/Lin-12/Glp-1 receptor family mediates the specification of numerous cell fates during development in Drosophila and Caenorhabditis elegans and putative components of the signaling cascade are identified, including a conserved family of extracellular ligands and two cellular factors that may associate with the Notch Intracellular domain.
Abstract: The Notch/Lin-12/Glp-1 receptor family mediates the specification of numerous cell fates during development in Drosophila and Caenorhabditis elegans. Studies on the expression, mutant phenotypes, and developmental consequences of unregulated receptor activation have implicated these proteins in a general mechanism of local cell signaling, which includes interactions between equivalent cells and between different cell types. Genetic approaches in flies and worms have identified putative components of the signaling cascade, including a conserved family of extracellular ligands and two cellular factors that may associate with the Notch Intracellular domain. One factor, the Drosophila Suppressor of Hairless protein, is a DNA-binding protein, which suggests that Notch signaling may involve relatively direct signal transmission from the cell surface to the nucleus. Several vertebrate Notch receptors have also been discovered recently and play important roles in normal development and tumorigenesis

1,240 citations

Journal ArticleDOI
TL;DR: Four distinct coding mutations in JAG1 are demonstrated, providing evidence that it is the causal gene for Alagille syndrome, and supporting the hypothesis that haploinsufficiency for this gene is one of the mechanisms causing the Alagile syndrome phenotype.
Abstract: Alagille syndrome is an autosomal dominant disorder characterized by abnormal development of liver, heart, skeleton, eye, face and, less frequently, kidney Analyses of many patients with cytogenetic deletions or rearrangements have mapped the gene to chromosome 20p12, although deletions are found in a relatively small proportion of patients (< 7%) We have mapped the human Jagged1 gene (JAG1), encoding a ligand for the developmentally important Notch transmembrane receptor, to the Alagille syndrome critical region within 20p12 The Notch intercellular signalling pathway has been shown to mediate cell fate decisions during development in invertebrates and vertebrates We demonstrate four distinct coding mutations in JAG1 from four Alagille syndrome families, providing evidence that it is the causal gene for Alagille syndrome All four mutations lie within conserved regions of the gene and cause translational frameshifts, resulting in gross alterations of the protein product Patients with cytogenetically detectable deletions including JAG1 have Alagille syndrome, supporting the hypothesis that haploinsufficiency for this gene is one of the mechanisms causing the Alagille syndrome phenotype

1,188 citations