Notch signaling pathway

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tumorigenesis in the urinary tract. As not all NOTCH receptors are equally involved in the urothelial bladder cancer, 90% of samples in one study had some level of NOTCH3 expression, suggesting that NOTCH3 plays an important role in urothelial bladder cancer. A higher level of NOTCH3 expression was observed in high-grade tumors, and a higher level of positivity was associated with a higher mortality risk. NOTCH3 was identified as an independent predictor of poor outcome. Therefore, it is suggested that NOTCH3 could be used as a marker for urothelial bladder cancer-specific mortality risk. It was also shown that NOTCH3 expression could be a prognostic immunohistochemical marker for clinical follow-up of urothelial bladder cancer patients, contributing to a more individualized approach by selecting patients to undergo control cystoscopy after a shorter time interval.

736:. In 1995, Notch1 was shown to be important for coordinating the segmentation of somites in mice. Further studies identified the role of Notch signaling in the segmentation clock. These studies hypothesized that the primary function of Notch signaling does not act on an individual cell, but coordinates cell clocks and keep them synchronized. This hypothesis explained the role of Notch signaling in the development of segmentation and has been supported by experiments in mice and zebrafish. Experiments with Delta1 mutant mice that show abnormal somitogenesis with loss of anterior/posterior polarity suggest that Notch signaling is also necessary for the maintenance of somite borders. 1142:

progressive recruitment of endocrine cell types from a common precursor, acting through two possible mechanisms. One is the "lateral inhibition", which specifies some cells for a primary fate but others for a secondary fate among cells that have the potential to adopt the same fate. Lateral inhibition is required for many types of cell fate determination. Here, it could explain the dispersed distribution of endocrine cells within pancreatic epithelium. A second mechanism is "suppressive maintenance", which explains the role of Notch signaling in pancreas differentiation. Fibroblast growth factor10 is thought to be important in this activity, but the details are unclear.

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role in selective recognition of Serrate/Jagged and EGF domains 6-15 are required for maximal signaling upon ligand stimulation. A crystal structure of the interacting regions of Notch1 and Delta-like 4 (Dll4) provided a molecular-level visualization of Notch-ligand interactions, and revealed that the N-terminal MNNL (or C2) and DSL domains of ligands bind to Notch EGF domains 12 and 11, respectively. The Notch1-Dll4 structure also illuminated a direct role for Notch O-linked fucose and glucose moieties in ligand recognition, and rationalized a structural mechanism for the glycan-mediated tuning of Notch signaling.

781: 1105:(Dll4), which is expressed in the endothelial tip cells. VEGF signaling, which is an important factor for migration and proliferation of endothelial cells, can be downregulated in cells with activated Notch signaling by lowering the levels of Vegf receptor transcript. Zebrafish embryos lacking Notch signaling exhibit ectopic and persistent expression of the zebrafish ortholog of VEGF3, flt4, within all endothelial cells, while Notch activation completely represses its expression. 32: 512: 20: 503:. It was originally thought that these CSL proteins suppressed Notch target transcription. However, further research showed that, when the intracellular domain binds to the complex, it switches from a repressor to an activator of transcription. Other proteins also participate in the intracellular portion of the notch signaling cascade. 888:, deletion of the Notch signaling modulator, Numb, disrupts neuronal maturation in the developing cerebellum, whereas deletion of Numb disrupts axonal arborization in sensory ganglia. Although the mechanism underlying this phenomenon is not clear, together these findings suggest Notch signaling might be crucial in neuronal maturation. 759:. Several key components of the Notch signaling pathway help coordinate key steps in this process. In mice, mutations in Notch1, Dll1 or Dll3, Lfng, or Hes7 result in abnormal somite formation. Similarly, in humans, the following mutations have been seen to lead to development of spondylocostal dysostosis: DLL3, LFNG, or HES7. 1116:

expression. In turn, DLL4 expressing cells down-regulate Vegf receptors in neighboring cells through activation of Notch, thereby preventing their migration into the developing sprout. Likewise, during the sprouting process itself, the migratory behavior of connector cells must be limited to retain a

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Maturation of the notch receptor involves cleavage at the prospective extracellular side during intracellular trafficking in the Golgi complex. This results in a bipartite protein, composed of a large extracellular domain linked to the smaller transmembrane and intracellular domain. Binding of ligand

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It is possible to engineer synthetic Notch receptors by replacing the extracellular receptor and intracellular transcriptional domains with other domains of choice. This allows researchers to select which ligands are detected, and which genes are upregulated in response. Using this technology, cells

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Despite the expansive size of the Notch extracellular domain, it has been demonstrated that EGF domains 11 and 12 are the critical determinants for interactions with Delta. Additional studies have implicated regions outside of Notch EGF11-12 in ligand binding. For example, Notch EGF domain 8 plays a

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The mathematical modeling of Notch-Delta signaling thus provides significant insights into lateral inhibition mechanisms and pattern formation in biological systems. It enhances the understanding of cell-cell interaction variations leading to diverse tissue structures, contributing to developmental

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The receptor is normally triggered via direct cell-to-cell contact, in which the transmembrane proteins of the cells in direct contact form the ligands that bind the notch receptor. The Notch binding allows groups of cells to organize themselves such that, if one cell expresses a given trait, this

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The Notch pathway is essential for maintaining NPCs in the developing brain. Activation of the pathway is sufficient to maintain NPCs in a proliferating state, whereas loss-of-function mutations in the critical components of the pathway cause precocious neuronal differentiation and NPC depletion.

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Apart from its role in development, evidence shows that Notch signaling is also involved in neuronal apoptosis, neurite retraction, and neurodegeneration of ischemic stroke in the brain In addition to developmental functions, Notch proteins and ligands are expressed in cells of the adult nervous

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sugar then the subsequent addition of a galactose and sialic acid will occur. In the presence of this tetrasaccharide, notch signals strongly when it interacts with the Delta ligand, but has markedly inhibited signaling when interacting with the Jagged ligand. The means by which this addition of

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is modified to include these protrusions, creating a more complex, non-local signaling network. This model is instrumental in exploring pattern formation robustness and biological pattern refinement, considering the stochastic nature of filopodia dynamics and intrinsic noise. The application of

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The role of Notch signaling in the regulation of gut development has been indicated in several reports. Mutations in elements of the Notch signaling pathway affect the earliest intestinal cell fate decisions during zebrafish development. Transcriptional analysis and gain of function experiments

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The formation of the pancreas from endoderm begins in early development. The expression of elements of the Notch signaling pathway have been found in the developing pancreas, suggesting that Notch signaling is important in pancreatic development. Evidence suggests Notch signaling regulates the

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Notch and most of its ligands are transmembrane proteins, so the cells expressing the ligands typically must be adjacent to the notch expressing cell for signaling to occur. The notch ligands are also single-pass transmembrane proteins and are members of the DSL (Delta/Serrate/LAG-2) family of

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Loss of Notch activity is a driving event in urothelial cancer. A study identified inactivating mutations in components of the Notch pathway in over 40% of examined human bladder carcinomas. In mouse models, genetic inactivation of Notch signaling results in Erk1/2 phosphorylation leading to

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during chondrogenesis. Overexpression of Notch signaling inhibits bone morphogenetic protein2-induced osteoblast differentiation. Overall, Notch signaling has a major role in the commitment of mesenchymal cells to the osteoblastic lineage and provides a possible therapeutic approach to bone

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Mathematical modeling in Notch-Delta signaling has become a pivotal tool in understanding pattern formation driven by cell-cell interactions, particularly in the context of lateral-inhibition mechanisms. The Collier model, a cornerstone in this field, employs a system of coupled

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can report or change their behavior in response to contact with user-specified signals, facilitating new avenues of both basic and applied research into cell-cell signaling. Notably, this system allows multiple synthetic pathways to be engineered into a cell in parallel.

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Notch 1, for example, has 36 of these repeats. Each EGF-like repeat is composed of approximately 40 amino acids, and its structure is defined largely by six conserved cysteine residues that form three conserved disulfide bonds. Each EGF-like repeat can be modified by

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To add another level of complexity, in mammals there are three Fringe GlcNAc-transferases, named lunatic fringe, manic fringe, and radical fringe. These enzymes are responsible for something called a "fringe effect" on notch signaling. If Fringe adds a GlcNAc to the

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The Notch signaling pathway is important for cell-cell communication, which involves gene regulation mechanisms that control multiple cell differentiation processes during embryonic and adult life. Notch signaling also has a role in the following processes:

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mutations would provoke Notch signaling pathway activation, fostering the cancer development, but a recent study demonstrated that such an effect cannot be detected. Thus the exact role of Notch signaling in the cancer process awaits further elucidation.

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1 and 2, which mediate the Notch intramembranous cleavage. To be specific, conditional deletion of presenilins at 3 weeks after birth in excitatory neurons causes learning and memory deficits, neuronal dysfunction, and gradual neurodegeneration. Several

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and by interendocardial signaling pathways to undergo EMT. Notch1 deficiency results in defective induction of EMT. Very few migrating cells are seen and these lack mesenchymal morphology. Notch may regulate this process by activating matrix

1294: 722:. During C. elegans, GLP-1, the C. elegans Notch homolog, interacts with APX-1, the C. elegans Delta homolog. This signaling between particular blastomeres induces differentiation of cell fates and establishes the dorsal-ventral axis. 1021:

expression in the AV canal endocardium while suppressing the VEGF pathway via VEGFR2. In RBPJk/CBF1-targeted mutants, the heart valve development is severely disrupted, presumably because of defective endocardial maturation and

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called ADAM10, cleaves the notch protein just outside the membrane. This releases the extracellular portion of notch (NECD), which continues to interact with the ligand. The ligand plus the notch extracellular domain is then

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Aberrant Notch signaling is a driver of T cell acute lymphoblastic leukemia (T-ALL) and is mutated in at least 65% of all T-ALL cases. Notch signaling can be activated by mutations in Notch itself, inactivating mutations in

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In adult rodents and in cell culture, Notch3 promotes neuronal differentiation, having a role opposite to Notch1/2. This indicates that individual Notch receptors can have divergent functions, depending on cellular context.

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Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S (November 1991). "Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor".

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indicate that Notch signaling has a major role in the induction of mesoderm and cell fate determination. As mentioned previously, C. elegans has two genes that encode for partially functionally redundant Notch homologs,

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may be switched off in neighbouring cells by the intercellular notch signal. In this way, groups of cells influence one another to make large structures. Thus, lateral inhibition mechanisms are key to Notch signaling.

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system, suggesting a role in CNS plasticity throughout life. Adult mice heterozygous for mutations in either Notch1 or Cbf1 have deficits in spatial learning and memory. Similar results are seen in experiments with

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by the ligand-expressing cell. There may be signaling effects in the ligand-expressing cell after endocytosis; this part of notch signaling is a topic of active research. After this first cleavage, an enzyme called

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During development of the aortic arch and the aortic arch arteries, the Notch receptors, ligands, and target genes display a unique expression pattern. When the Notch pathway was blocked, the induction of vascular

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Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J (August 1991). "TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms".

1059:, whereby upregulated Wnt expression downregulates Notch signaling, and a subsequent inhibition of ventricular cardiomyocyte proliferation results. This proliferative arrest can be rescued using Wnt inhibitors. 264:, as well as intracellular proteins transmitting the notch signal to the cell's nucleus. The Notch/Lin-12/Glp-1 receptor family was found to be involved in the specification of cell fates during development in 771:

works in conjunction with ARF4 to regulate Notch signaling during this development. However, it remains to be determined whether gamma-secretase has a direct or indirect role in modulating Notch signaling.

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promotes two proteolytic processing events; as a result of proteolysis, the intracellular domain is liberated and can enter the nucleus to engage other DNA-binding proteins and regulate gene expression.

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Lawson ND, Scheer N, Pham VN, Kim CH, Chitnis AB, Campos-Ortega JA, Weinstein BM (October 2001). "Notch signaling is required for arterial-venous differentiation during embryonic vascular development".

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Götte M, Wolf M, Staebler A, Buchweitz O, Kelsch R, Schüring AN, Kiesel L (July 2008). "Increased expression of the adult stem cell marker Musashi-1 in endometriosis and endometrial carcinoma".

1299: 335:. There has been at least one report that suggests that some cells can send out processes that allow signaling to occur between cells that are as much as four or five cell diameters apart. 4689:

van Eeden FJ, Granato M, Schach U, Brand M, Furutani-Seiki M, Haffter P, et al. (December 1996). "Mutations affecting somite formation and patterning in the zebrafish, Danio rerio".

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A non-canonical branch of the Notch signaling pathway that involves the phosphorylation of STAT3 on the serine residue at amino acid position 727 and subsequent Hes3 expression increase (

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Hellström M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, et al. (February 2007). "Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis".

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Zhong W, Jiang MM, Weinmaster G, Jan LY, Jan YN (May 1997). "Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis".

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Shao L, Luo Y, Moloney DJ, Haltiwanger R (November 2002). "O-glycosylation of EGF repeats: identification and initial characterization of a UDP-glucose: protein O-glucosyltransferase".

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differentiates into several gastrointestinal epithelial lineages, including endocrine cells. Many studies have indicated that Notch signaling has a major role in endocrine development.

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and in mouse embryonic stem cells indicate that cardiomyogenic commitment and differentiation require Notch signaling inhibition. Active Notch signaling is required in the ventricular

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Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, et al. (October 2004). "Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia".

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cell marker expression failed to occur, suggesting that Notch is involved in the differentiation of cardiac neural crest cells into vascular cells during outflow tract development.

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Notch signaling is required in the regulation of polarity. For example, mutation experiments have shown that loss of Notch signaling causes abnormal anterior-posterior polarity in

1008:, which is required for AV canal maturation. After the AV canal boundary formation, a subset of endocardial cells lining the AV canal are activated by signals emanating from the 8037:

Eisen JS (2010-07-27). "Faculty Opinions recommendation of Dynamic filopodia transmit intermittent Delta-Notch signaling to drive pattern refinement during lateral inhibition".

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Watanabe N, Tezuka Y, Matsuno K, Miyatani S, Morimura N, Yasuda M, et al. (2003). "Suppression of differentiation and proliferation of early chondrogenic cells by Notch".

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Rampias T, Vgenopoulou P, Avgeris M, Polyzos A, Stravodimos K, Valavanis C, et al. (October 2014). "A new tumor suppressor role for the Notch pathway in bladder cancer".

1194:(a negative regulator of Notch1), or rarely by t(7;9)(q34;q34.3) translocation. In the context of T-ALL, Notch activity cooperates with additional oncogenic lesions such as 1711: 755:. This process is highly regulated as somites must have the correct size and spacing in order to avoid malformations within the axial skeleton that may potentially lead to 767:

Notch signaling is known to occur inside ciliated, differentiating cells found in the first epidermal layers during early skin development. Furthermore, it has found that

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The downstream effector of Notch signaling, HEY2, was also demonstrated to be important in regulating ventricular development by its expression in the interventricular

1070:. Cardiomyocyte and smooth muscle cell-specific deletion of HEY2 results in impaired cardiac contractility, malformed right ventricle, and ventricular septal defects. 934:

patients resulted in statistically significant worsening of cognition relative to controls, which is thought to be due to its incidental effect on Notch signalling.

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embryos. In the past decade, advances in mutation and knockout techniques allowed research on the Notch signaling pathway in mammalian models, especially rodents.

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Activation of Notch takes place primarily in "connector" cells and cells that line patent stable blood vessels through direct interaction with the Notch ligand,

3927:"Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis" 1638: 1581: 1561: 1541: 988:

Studies have revealed that both loss- and gain-of-function of the Notch pathway results in defects in AV canal development. In addition, the Notch target genes

405:-fucose, all notch proteins fail to function properly. As yet, the manner by which the glycosylation of notch affects function is not completely understood. 241:

by Gary Struhl and in cell culture by Raphael Kopan. Although this model was initially disputed, the evidence in favor of the model was irrefutable by 2001.

2472:"Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei" 1747:

mathematical modeling in Notch-Delta signaling has been particularly illuminating in understanding the patterning of sensory organ precursors (SOPs) in the

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Notch signaling is dysregulated in many cancers, and faulty notch signaling is implicated in many diseases, including T-cell acute lymphoblastic leukemia (

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Rones MS, McLaughlin KA, Raffin M, Mercola M (September 2000). "Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis".

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cells at the expense of neurons, whereas reduced Notch signaling induces production of ganglion cells, causing a reduction in the number of Muller glia.

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Jensen J, Pedersen EE, Galante P, Hald J, Heller RS, Ishibashi M, et al. (January 2000). "Control of endodermal endocrine development by Hes-1".

1456:{\displaystyle {\begin{aligned}{\frac {d}{dt}}n_{i}&=f(\langle d_{i}\rangle )-n_{i}\\{\frac {d}{dt}}d_{i}&=\nu (g(n_{i})-d_{i})\end{aligned}}} 8679: 8231: 6869:

Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, et al. (August 1999). "Notch signalling controls pancreatic cell differentiation".

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Vasilopoulos G, Painter KJ (March 2016). "Pattern formation in discrete cell tissues under long range filopodia-based direct cell to cell contact".

3219:"The glycosyltransferase Fringe promotes Delta-Notch signaling between neurons and glia, and is required for subtype-specific glial gene expression" 1108:

Notch signaling may be used to control the sprouting pattern of blood vessels during angiogenesis. When cells within a patent vessel are exposed to

3260:"The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments" 2294:

Austin J, Kimble J (November 1987). "glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans".

1258:, a disease characterised by increased expression of notch pathway constituents. Several notch inhibitors, including the gamma-secretase inhibitor 1151:

revealed that Notch signaling targets Hes1 in the intestine and regulates a binary cell fate decision between adsorptive and secretory cell fates.

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Scheer N, Groth A, Hans S, Campos-Ortega JA (April 2001). "An instructive function for Notch in promoting gliogenesis in the zebrafish retina".

8287: 6383:"Essential roles of the bHLH transcription factor Hrt2 in repression of atrial gene expression and maintenance of postnatal cardiac function" 124:. Inhibition of notch signaling inhibits the proliferation of T-cell acute lymphoblastic leukemia in both cultured cells and a mouse model. 2647:

Schroeter EH, Kisslinger JA, Kopan R (May 1998). "Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain".

2158:"Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats" 311: 5066:

Redmond L, Oh SR, Hicks C, Weinmaster G, Ghosh A (January 2000). "Nuclear Notch1 signaling and the regulation of dendritic development".

4726:"Analysis of Notch function in presomitic mesoderm suggests a gamma-secretase-independent role for presenilins in somite differentiation" 1259: 1246:) as cancer treatments which are in different phases of clinical trials. As of 2013 at least 7 notch inhibitors were in clinical trials. 94:

interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small

8081:"The importance of structured noise in the generation of self-organizing tissue patterns through contact-mediated cell-cell signalling" 6963:

Field HA, Dong PD, Beis D, Stainier DY (September 2003). "Formation of the digestive system in zebrafish. II. Pancreas morphogenesis".

7506:"Unraveling the impact of AXIN1 mutations on HCC development: Insights from CRISPR/Cas9 repaired AXIN1-mutant liver cancer cell lines" 2199:"Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors" 842:

protein are able to antagonize Notch effects, resulting in the halting of cell cycle and the differentiation of NPCs. Conversely, the

4142:"Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling" 4025: 1247: 398: 387: 379: 318:. In mammals there are multiple Delta-like and Jagged ligands, as well as possibly a variety of other ligands, such as F3/contactin. 8779: 4638:

Hrabĕ de Angelis M, McIntyre J, Gossler A (April 1997). "Maintenance of somite borders in mice requires the Delta homologue DII1".

4450:"Noncyclic Notch activity in the presomitic mesoderm demonstrates uncoupling of somite compartmentalization and boundary formation" 4391:"REX-1 expression and p38 MAPK activation status can determine proliferation/differentiation fates in human mesenchymal stem cells" 208:

proteins binding to the extracellular domain induce proteolytic cleavage and release of the intracellular domain, which enters the

2854:"The C. elegans spe-9 gene encodes a sperm transmembrane protein that contains EGF-like repeats and is required for fertilization" 8246: 1796:

Artavanis-Tsakonas S, Rand MD, Lake RJ (April 1999). "Notch signaling: cell fate control and signal integration in development".

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Zhang R, Li S, Schippers K, Eimers B, Niu J, Hornung BV, van den Hout MC, van Ijcken WF, Peppelenbosch MP, Smits R (June 2024).

9302: 8181:"Coordinated control of Notch/Delta signalling and cell cycle progression drives lateral inhibition-mediated tissue patterning" 515:

Crystal structure of the Notch1-DLL4 complex depicted as the interaction is predicted to occur between two cells (PDB ID: 4XLW)

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Siekmann AF, Lawson ND (February 2007). "Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries".

5625:"Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration" 116:), cerebral autosomal-dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL), multiple sclerosis, 8672: 8145: 7572: 5730: 4584: 2511:

Struhl G, Fitzgerald K, Greenwald I (July 1993). "Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo".

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The Notch signaling pathway plays an important role in cell-cell communication, and further regulates embryonic development.

3005:"The notch signalling regulator fringe acts in the Golgi apparatus and requires the glycosyltransferase signature motif DXD" 2337:

Priess JR, Schnabel H, Schnabel R (November 1987). "The glp-1 locus and cellular interactions in early C. elegans embryos".

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Greenwald IS, Sternberg PW, Horvitz HR (September 1983). "The lin-12 locus specifies cell fates in Caenorhabditis elegans".

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are involved in restricting the expression of two critical developmental regulator proteins, BMP2 and Tbx2, to the AV canal.

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has given promising results in an early clinical trial for breast cancer. Preclinical studies showed beneficial effects of

8132:. Advances in Experimental Medicine and Biology. Vol. 1066. Cham: Springer International Publishing. pp. 79–98. 7355:"NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth" 5580:

Presente A, Andres A, Nye JS (October 2001). "Requirement of Notch in adulthood for neurological function and longevity".

5206:"Inactivation of Numb and Numblike in embryonic dorsal forebrain impairs neurogenesis and disrupts cortical morphogenesis" 821:(NPC) maintenance and self-renewal. In recent years, other functions of the Notch pathway have also been found, including 492:

of the notch-expressing cell. This releases the intracellular domain of the notch protein (NICD), which then moves to the

9267: 8534: 5985:"Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation" 7864:"Therapeutic Potential of Wnt and Notch Signaling and Epigenetic Regulation in Mammalian Sensory Hair Cell Regeneration" 253:

mediate binary cell fate decisions, and lateral inhibition involves feedback mechanisms to amplify initial differences.

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influencing of binary fate decisions of cells that must choose between the secretory and absorptive lineages in the gut

2382:"lin-12, a nematode homeotic gene, is homologous to a set of mammalian proteins that includes epidermal growth factor" 8812: 8280: 7913:"Pattern formation by lateral inhibition with feedback: a mathematical model of delta-notch intercellular signalling" 7169:"Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells" 7084:"FGF10 signaling maintains the pancreatic progenitor cell state revealing a novel role of Notch in organ development" 5851:"Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2" 3193: 1094:

cells use the Notch signaling pathway to coordinate cellular behaviors during the blood vessel sprouting that occurs

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Notch signaling can regulate the atrioventricular boundary formation between the AV canal and the chamber myocardium.

9069: 8855: 8850: 8665: 3878:"Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells" 784:

Notch-Delta lateral inhibition in neural stem cells, resulting in the generation of neuronal and glial progenitors.

5498:"Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborization" 4810:"Stimulation of human epidermal differentiation by delta-notch signalling at the boundaries of stem-cell clusters" 4183:"Signaling axis involving Hedgehog, Notch, and Scl promotes the embryonic endothelial-to-hematopoietic transition" 1647:

Recent extensions of this model incorporate long-range signaling, acknowledging the role of cell protrusions like

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sugar inhibits signaling through one ligand, and potentiates signaling through another is not clearly understood.

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Ristic Petrovic A, Stokanović D, Stojnev S, Potić Floranović M, Krstić M, Djordjević I, et al. (July 2022).

6745:"Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family" 6442:"An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation" 5802:"Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors" 4765:

Wahi K, Bochter MS, Cole SE (January 2016). "The many roles of Notch signaling during vertebrate somitogenesis".

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Lambie EJ, Kimble J (May 1991). "Two homologous regulatory genes, lin-12 and glp-1, have overlapping functions".

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to activate anabolic pathways such as ribosome and protein biosynthesis thereby promoting leukemia cell growth.

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may be added between the second and third conserved cysteines. These sugars are added by an as-yet-unidentified

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in the proliferative state, amounting to a mechanism regulating cortical surface area growth and, potentially,

9246: 7457:"The association between NOTCH3 expression and the clinical outcome in the urothelial bladder cancer patients" 6100:

Croquelois A, Domenighetti AA, Nemir M, Lepore M, Rosenblatt-Velin N, Radtke F, Pedrazzini T (December 2008).

5944:"VE-cadherin is not required for the formation of nascent blood vessels but acts to prevent their disassembly" 9097: 4603:

Conlon RA, Reaume AG, Rossant J (May 1995). "Notch1 is required for the coordinate segmentation of somites".

1891:"A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE" 9321: 8529: 8273: 5351:

Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, et al. (August 2006).

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was associated with Notch dysfunction indicated that Notch mutations can lead to the failure of neural and

5895:"Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation" 2130: 9064: 7912: 7682:"γ-Secretase inhibition affects viability, apoptosis, and the stem cell phenotype of endometriotic cells" 7680:

Ramirez Williams L, Brüggemann K, Hubert M, Achmad N, Kiesel L, Schäfer SD, et al. (December 2019).

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Campa VM, Gutiérrez-Lanza R, Cerignoli F, Díaz-Trelles R, Nelson B, Tsuji T, et al. (October 2008).

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Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, et al. (April 2004).

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Woo HN, Park JS, Gwon AR, Arumugam TV, Jo DG (December 2009). "Alzheimer's disease and Notch signaling".

2907:"Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes" 1052: 9256: 9122: 8954: 8348: 8331: 8314: 7083: 613: 6581:

Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, Wiegand SJ (February 2007).

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Timmerman LA, Grego-Bessa J, Raya A, Bertrán E, Pérez-Pomares JM, Díez J, et al. (January 2004).

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Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, et al. (November 2009).

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biology and offering potential therapeutic pathways in diseases related to Notch-Delta dysregulation.

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to promote neural differentiation. It plays a major role in the regulation of embryonic development.

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Grego-Bessa J, Luna-Zurita L, del Monte G, Bolós V, Melgar P, Arandilla A, et al. (March 2007).

1067: 931: 756: 748: 147: 7314: 6920:

Lammert E, Brown J, Melton DA (June 2000). "Notch gene expression during pancreatic organogenesis".

2752:"Presenilin-mediated transmembrane cleavage is required for Notch signal transduction in Drosophila" 1112:

signaling, only a restricted number of them initiate the angiogenic process. Vegf is able to induce

8636: 8326: 8259: 1678: 1216: 843: 5255:"FGF signaling expands embryonic cortical surface area by regulating Notch-dependent neurogenesis" 4978:"rax, Hes1, and notch1 promote the formation of Müller glia by postnatal retinal progenitor cells" 900:, Notch appears to have an instructive role that can directly promote the differentiation of many 9190: 9102: 8985: 8905: 8700: 8464: 8436: 8363: 4867:"A Presenilin-2-ARF4 trafficking axis modulates Notch signaling during epidermal differentiation" 4497:

Levin M (January 2005). "Left-right asymmetry in embryonic development: a comprehensive review".

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in mammals and zebrafish. A regulatory correspondence likely exists between Notch signaling and

602: 339: 298: 134: 6786:"Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function" 6247:

Zhao L, Borikova AL, Ben-Yair R, Guner-Ataman B, MacRae CA, Lee RT, et al. (January 2014).

3176:

Lu L, Stanley P (2006). "Roles of O-Fucose Glycans in Notch Signaling Revealed by Mutant Mice".

3106:

Ma B, Simala-Grant JL, Taylor DE (December 2006). "Fucosylation in prokaryotes and eukaryotes".

1171:. Notch1 is expressed in the mesenchymal condensation area and subsequently in the hypertrophic 609:

lineage, suggesting a potential therapeutic role for notch in bone regeneration and osteoporosis

9175: 9074: 9059: 9028: 8929: 8476: 8449: 8128:

Binshtok U, Sprinzak D (2018). "Modeling the Notch Response". In Borggrefe T, Giaimo B (eds.).

7811:

Erni ST, Gill JC, Palaferri C, Fernandes G, Buri M, Lazarides K, et al. (13 August 2021).

7309: 7126:

Crosnier C, Vargesson N, Gschmeissner S, Ariza-McNaughton L, Morrison A, Lewis J (March 2005).

6583:"Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting" 3738:

Gaiano N, Fishell G (2002). "The role of notch in promoting glial and neural stem cell fates".

1658: 1095: 971: 967: 955: 927: 789: 708: 519:

Notch signaling is initiated when Notch receptors on the cell surface engage ligands presented

485: 323: 156: 8065: 700:. Also, Notch signaling is required during left-right asymmetry determination in vertebrates. 9286: 9180: 9107: 9006: 8944: 8939: 8870: 8805: 8732: 8657: 8602: 8564: 8444: 8390: 8368: 8321: 7721:

Schüring AN, Dahlhues B, Korte A, Kiesel L, Titze U, Heitkötter B, et al. (March 2018).

6332:

Wang J, Sridurongrit S, Dudas M, Thomas P, Nagy A, Schneider MD, et al. (October 2005).

2421:

Oswald F, Täuber B, Dobner T, Bourteele S, Kostezka U, Adler G, et al. (November 2001).

1843: 1641: 1056: 858:. In this way, Notch signaling controls NPC self-renewal as well as cell fate specification. 677: 283:

to activate transcription of target genes. The structure of the complex has been determined.

261: 205: 75: 24: 1291:

to describe the feedback loop between adjacent cells. The model is defined by the equations:

904:

subtypes. For example, activation of Notch signaling in the retina favors the generation of

9195: 9038: 9033: 8915: 8910: 8897: 8573: 8569: 8521: 8255: 7924: 7366: 7301: 7167:

Yamada T, Yamazaki H, Yamane T, Yoshino M, Okuyama H, Tsuneto M, et al. (March 2003).

7128:"Delta-Notch signalling controls commitment to a secretory fate in the zebrafish intestine" 6878: 6649: 6594: 6498: 6394: 6334:"Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart" 6260: 6249:"Notch signaling regulates cardiomyocyte proliferation during zebrafish heart regeneration" 6061:"Induction of cardiogenesis in embryonic stem cells via downregulation of Notch1 signaling" 5364: 5125: 4927: 4821: 4647: 4402: 4291:"Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells" 4194: 4050: 3832: 3751: 3555: 3482: 3299:

van Tetering G, van Diest P, Verlaan I, van der Wall E, Kopan R, Vooijs M (November 2009).

3016: 2818: 2763: 2656: 2041: 1984: 1805: 1495: 1468: 966:

Notch signal pathway plays a crucial role in at least three cardiac development processes:

780: 497: 7813:"Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors" 5942:

Crosby CV, Fleming PA, Argraves WS, Corada M, Zanetta L, Dejana E, Drake CJ (April 2005).

5408:"Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord" 865:) has been shown to regulate the number of NPCs in culture and in the adult rodent brain. 8: 9291: 8688: 8631: 8614: 8300: 7353:

Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A, et al. (November 2006).

6381:

Xin M, Small EM, van Rooij E, Qi X, Richardson JA, Srivastava D, et al. (May 2007).

6308:"An Evolving Role for Notch Signaling in Heart Regeneration of the Zebrafish Danio rerio" 6102:"Control of the adaptive response of the heart to stress via the Notch1 receptor pathway" 5983:

Noseda M, McLean G, Niessen K, Chang L, Pollet I, Montpetit R, et al. (April 2004).

862: 807: 432: 428: 338:

The notch extracellular domain is composed primarily of small cystine-rich motifs called

117: 7928: 7532: 7505: 7370: 7305: 6882: 6653: 6598: 6540:

Leslie JD, Ariza-McNaughton L, Bermange AL, McAdow R, Johnson SL, Lewis J (March 2007).

6502: 6398: 6264: 5368: 5204:

Li HS, Wang D, Shen Q, Schonemann MD, Gorski JA, Jones KR, et al. (December 2003).

5129: 4931: 4825: 4651: 4406: 4340:

Guseh JS, Bores SA, Stanger BZ, Zhou Q, Anderson WJ, Melton DA, Rajagopal J (May 2009).

4198: 4140:

Nobta M, Tsukazaki T, Shibata Y, Xin C, Moriishi T, Sakano S, et al. (April 2005).

4054: 3876:

Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia AJ, Nye JS, et al. (April 2002).

3836: 3559: 3486: 3020: 2822: 2767: 2660: 2045: 1988: 1889:

Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, et al. (February 2000).

1809: 132:

In 1914, John S. Dexter noticed the appearance of a notch in the wings of the fruit fly

8980: 8373: 8265: 8205: 8180: 8156: 8105: 8080: 7888: 7863: 7839: 7812: 7793: 7750: 7632: 7607: 7583: 7481: 7456: 7437: 7389: 7354: 7335: 7233: 7023: 6945: 6902: 6810: 6785: 6720: 6695: 6673: 6617: 6582: 6522: 6466: 6441: 6440:

High FA, Zhang M, Proweller A, Tu L, Parmacek MS, Pear WS, Epstein JA (February 2007).

6417: 6382: 6358: 6333: 6283: 6248: 6224: 6199: 6175: 6150: 6126: 6101: 6077: 6060: 6001: 5984: 5826: 5801: 5654: 5605: 5432: 5407: 5388: 5328: 5303: 5279: 5254: 5235: 5151: 5091: 5007: 4950: 4915: 4891: 4866: 4847: 4790: 4671: 4522: 4474: 4449: 4425: 4390: 4366: 4341: 4317: 4290: 4266: 4241: 4217: 4182: 4003: 3978: 3853: 3821:"Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal" 3820: 3715: 3690: 3666: 3641: 3576: 3543: 3506: 3454: 3327: 3300: 3088: 3042: 2985: 2936: 2883: 2727: 2702: 2680: 2629: 2580: 2536: 2362: 2319: 2271: 2111: 2085: 2067: 2005: 1972: 1871: 1623: 1566: 1546: 1526: 1039:

for proper trabeculae development subsequent to myocardial specification by regulating

659: 589: 488:) cleaves the remaining part of the notch protein just inside the inner leaflet of the 412:-glucose on notch can be further elongated to a trisaccharide with the addition of two 143: 44: 8240: 8179:

Hunter GL, Hadjivasiliou Z, Bonin H, He L, Perrimon N, Charras G, Baum B (July 2016).

7723:"The endometrial stem cell markers notch-1 and numb are associated with endometriosis" 7656:"Notch inhibitors could help overcome therapy resistance in ER-positive breast cancer" 6976: 6933: 6761: 6744: 5919: 5894: 5641: 5624: 5522: 5497: 5222: 5205: 5138: 5113: 4994: 4977: 4834: 4809: 4073: 4038: 3951: 3926: 3902: 3877: 3185: 3029: 3004: 2870: 2853: 2616: 2599: 2223: 2198: 1907: 1890: 751:

has been proposed in order to spatially determine the location and boundaries between

585:, as well as implications in other human disorders involving the cardiovascular system 9241: 9021: 9016: 8925: 8481: 8210: 8161: 8141: 8110: 8052: 8019: 7984: 7940: 7893: 7844: 7797: 7785: 7742: 7703: 7637: 7623: 7588: 7568: 7537: 7486: 7429: 7394: 7327: 7274: 7225: 7190: 7149: 7105: 7064: 7015: 6980: 6937: 6894: 6851: 6815: 6766: 6725: 6665: 6622: 6563: 6514: 6471: 6422: 6363: 6307: 6288: 6229: 6180: 6131: 6082: 6041: 6006: 5965: 5924: 5872: 5831: 5782: 5736: 5726: 5695: 5646: 5597: 5593: 5562: 5527: 5478: 5437: 5380: 5333: 5284: 5227: 5186: 5143: 5083: 5045: 4999: 4955: 4896: 4839: 4782: 4747: 4706: 4663: 4620: 4580: 4557: 4514: 4479: 4430: 4371: 4342:"Notch signaling promotes airway mucous metaplasia and inhibits alveolar development" 4322: 4271: 4222: 4163: 4119: 4078: 4008: 3956: 3907: 3858: 3801: 3755: 3720: 3671: 3622: 3581: 3498: 3494: 3446: 3442: 3410: 3367: 3332: 3281: 3240: 3199: 3189: 3158: 3123: 3080: 3063:

Lai EC (March 2004). "Notch signaling: control of cell communication and cell fate".

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gene. Compelling evidence for this model was provided in 1998 by in vivo analysis in

146:. Its molecular analysis and sequencing was independently undertaken in the 1980s by 121: 9225: 7339: 7027: 5658: 5155: 5095: 5011: 4794: 4526: 4181:

Kim PG, Albacker CE, Lu YF, Jang IH, Lim Y, Heffner GC, et al. (January 2013).

3510: 3458: 3046: 2940: 2887: 2633: 2584: 2540: 2323: 2275: 2115: 1875: 942:

The Notch signaling pathway is a critical component of cardiovascular formation and

9251: 9220: 9215: 9170: 8798: 8607: 8578: 8507: 8403: 8336: 8200: 8192: 8151: 8133: 8100: 8092: 8038: 8011: 7974: 7932: 7883: 7875: 7834: 7824: 7777: 7754: 7734: 7693: 7627: 7619: 7578: 7560: 7527: 7517: 7476: 7468: 7441: 7421: 7384: 7374: 7319: 7264: 7237: 7217: 7180: 7139: 7095: 7054: 7007: 6972: 6949: 6929: 6906: 6886: 6843: 6805: 6797: 6756: 6715: 6707: 6677: 6657: 6612: 6602: 6553: 6526: 6506: 6461: 6453: 6412: 6402: 6353: 6345: 6278: 6268: 6219: 6211: 6170: 6162: 6121: 6113: 6072: 6033: 5996: 5955: 5914: 5906: 5862: 5821: 5813: 5772: 5718: 5685: 5636: 5609: 5589: 5554: 5517: 5509: 5496:

Huang EJ, Li H, Tang AA, Wiggins AK, Neve RL, Zhong W, et al. (January 2005).

5468: 5427: 5419: 5392: 5372: 5323: 5319: 5315: 5274: 5270: 5266: 5239: 5217: 5178: 5133: 5075: 5037: 4989: 4945: 4935: 4916:"Chromosomal Deficiencies and the Embryonic Development of Drosophila Melanogaster" 4886: 4878: 4851: 4829: 4774: 4737: 4698: 4675: 4655: 4612: 4549: 4506: 4469: 4461: 4420: 4410: 4361: 4353: 4312: 4302: 4261: 4253: 4212: 4202: 4153: 4109: 4068: 4058: 3998: 3990: 3946: 3938: 3897: 3889: 3848: 3840: 3791: 3747: 3710: 3702: 3661: 3653: 3612: 3571: 3563: 3490: 3438: 3400: 3359: 3322: 3312: 3271: 3230: 3181: 3150: 3115: 3092: 3072: 3024: 2989: 2967: 2918: 2865: 2826: 2781: 2771: 2722: 2714: 2684: 2664: 2611: 2564: 2520: 2483: 2442: 2434: 2393: 2366: 2346: 2303: 2255: 2218: 2210: 2169: 2103: 2049: 2000: 1992: 1943: 1902: 1855: 1813: 151: 7559:. Advances in Experimental Medicine and Biology. Vol. 727. pp. 305–319. 7555:

Purow B (2012). "Notch Inhibition as a Promising New Approach to Cancer Therapy".

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Bhandari DR, Seo KW, Roh KH, Jung JW, Kang SK, Kang KS (May 2010). Pera M (ed.).

3994: 3657: 1859: 1817: 1655:) that reach non-neighboring cells. One extended model, often referred to as the 1251: 1233: 946:

in both development and disease. It is required for the selection of endothelial

923: 851: 818: 643: 612:

expansion of the hemogenic endothelial cells along with signaling axis involving

481: 471: 315: 213: 79: 8137: 7879: 7454: 7100: 6542:"Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis" 6349: 6200:"Notch activates cell cycle reentry and progression in quiescent cardiomyocytes" 5800:

Rutenberg JB, Fischer A, Jia H, Gessler M, Zhong TP, Mercola M (November 2006).

5473: 5456: 5304:"Cortical gyrification induced by fibroblast growth factor 2 in the mouse brain" 3942: 3925:

Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, et al. (January 2003).

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