notch signaling pathway

In 1914, John S. Dexter noticed the appearance of a notch in the wings of the fruit fly Drosophila melanogaster. The alleles of the gene were identified in 1917 by American evolutionary biologist Thomas Hunt Morgan.{{Cite journal | vauthors = Morgan TH | author-link = Thomas Hunt Morgan | year = 1917 | title = The theory of the gene | journal = The American Naturalist | volume=51 | issue=609 | pages = 513–544 | doi=10.1086/279629 | bibcode = 1917ANat...51..513M | s2cid = 84050307 | url = https://zenodo.org/record/1431357 }}{{cite book | vauthors = Morgan TH | title = The theory of the gene | edition = revised | publisher = Yale University Press | year = 1928 | pages = 77–81 | url = http://onlinebooks.library.upenn.edu/webbin/book/lookupid?key=olbp24097 | isbn = 978-0-8240-1384-4 }} Its molecular analysis and sequencing was independently undertaken in the 1980s by Spyros Artavanis-Tsakonas and Michael W. Young.{{cite journal | vauthors = Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S | title = Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats | journal = Cell | volume = 43 | issue = 3 Pt 2 | pages = 567–581 | date = December 1985 | pmid = 3935325 | doi = 10.1016/0092-8674(85)90229-6 | doi-access = free }}{{cite journal | vauthors = Kidd S, Kelley MR, Young MW | title = Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors | journal = Molecular and Cellular Biology | volume = 6 | issue = 9 | pages = 3094–3108 | date = September 1986 | pmid = 3097517 | pmc = 367044 | doi = 10.1128/mcb.6.9.3094 }} Alleles of the two C. elegans Notch genes were identified based on developmental phenotypes: lin-12{{cite journal | vauthors = Greenwald IS, Sternberg PW, Horvitz HR | title = The lin-12 locus specifies cell fates in Caenorhabditis elegans | journal = Cell | volume = 34 | issue = 2 | pages = 435–444 | date = September 1983 | pmid = 6616618 | doi = 10.1016/0092-8674(83)90377-x | s2cid = 40668388 }} and glp-1.{{cite journal | vauthors = Austin J, Kimble J | title = glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans | journal = Cell | volume = 51 | issue = 4 | pages = 589–599 | date = November 1987 | pmid = 3677168 | doi = 10.1016/0092-8674(87)90128-0 | s2cid = 31484517 }}{{cite journal | vauthors = Priess JR, Schnabel H, Schnabel R | title = The glp-1 locus and cellular interactions in early C. elegans embryos | journal = Cell | volume = 51 | issue = 4 | pages = 601–611 | date = November 1987 | pmid = 3677169 | doi = 10.1016/0092-8674(87)90129-2 | s2cid = 6282210 }} The cloning and partial sequence of lin-12 was reported at the same time as Drosophila Notch by Iva Greenwald.{{cite journal | vauthors = Greenwald I | title = lin-12, a nematode homeotic gene, is homologous to a set of mammalian proteins that includes epidermal growth factor | journal = Cell | volume = 43 | issue = 3 Pt 2 | pages = 583–590 | date = December 1985 | pmid = 3000611 | doi = 10.1016/0092-8674(85)90230-2 | doi-access = free }}

{{further|Notch protein}}

The Notch protein spans the cell membrane, with part of it inside and part outside. Ligand proteins binding to the extracellular domain induce proteolytic cleavage and release of the intracellular domain, which enters the cell nucleus to modify gene expression.{{cite journal | vauthors = Oswald F, Täuber B, Dobner T, Bourteele S, Kostezka U, Adler G, Liptay S, Schmid RM | display-authors = 6 | title = p300 acts as a transcriptional coactivator for mammalian Notch-1 | journal = Molecular and Cellular Biology | volume = 21 | issue = 22 | pages = 7761–7774 | date = November 2001 | pmid = 11604511 | pmc = 99946 | doi = 10.1128/MCB.21.22.7761-7774.2001 }}

The cleavage model was first proposed in 1993 based on work done with Drosophila Notch and C. elegans lin-12,{{cite journal | vauthors = Lieber T, Kidd S, Alcamo E, Corbin V, Young MW | title = Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei | journal = Genes & Development | volume = 7 | issue = 10 | pages = 1949–1965 | date = October 1993 | pmid = 8406001 | doi = 10.1101/gad.7.10.1949 | doi-access = free }}{{cite journal | vauthors = Struhl G, Fitzgerald K, Greenwald I | title = Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo | journal = Cell | volume = 74 | issue = 2 | pages = 331–345 | date = July 1993 | pmid = 8343960 | doi = 10.1016/0092-8674(93)90424-O | s2cid = 27966283 }} informed by the first oncogenic mutation affecting a human Notch gene.{{cite journal | vauthors = Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J | title = TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms | journal = Cell | volume = 66 | issue = 4 | pages = 649–661 | date = August 1991 | pmid = 1831692 | doi = 10.1016/0092-8674(91)90111-B | s2cid = 45604279 }} Compelling evidence for this model was provided in 1998 by in vivo analysis in Drosophila by Gary Struhl{{cite journal | vauthors = Struhl G, Adachi A | title = Nuclear access and action of notch in vivo | journal = Cell | volume = 93 | issue = 4 | pages = 649–660 | date = May 1998 | pmid = 9604939 | doi = 10.1016/S0092-8674(00)81193-9 | s2cid = 10828910 | doi-access = free }} and in cell culture by Raphael Kopan.{{cite journal | vauthors = Schroeter EH, Kisslinger JA, Kopan R | title = Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain | journal = Nature | volume = 393 | issue = 6683 | pages = 382–386 | date = May 1998 | pmid = 9620803 | doi = 10.1038/30756 | s2cid = 4431882 | bibcode = 1998Natur.393..382S }} Although this model was initially disputed, the evidence in favor of the model was irrefutable by 2001.{{cite journal | vauthors = Greenwald I | title = Notch and the awesome power of genetics | journal = Genetics | volume = 191 | issue = 3 | pages = 655–669 | date = July 2012 | pmid = 22785620 | pmc = 3389966 | doi = 10.1534/genetics.112.141812 }}{{cite journal | vauthors = Struhl G, Greenwald I | title = Presenilin-mediated transmembrane cleavage is required for Notch signal transduction in Drosophila | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 1 | pages = 229–234 | date = January 2001 | pmid = 11134525 | pmc = 14573 | doi = 10.1073/pnas.98.1.229 | doi-access = free | bibcode = 2001PNAS...98..229S }}

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 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. lin-12 and Notch mediate binary cell fate decisions, and lateral inhibition involves feedback mechanisms to amplify initial differences.

The Notch cascade consists of Notch and Notch ligands, as well as intracellular proteins transmitting the notch signal to the cell's nucleus. The Notch/Lin-12/Glp-1 receptor family{{cite journal | vauthors = Artavanis-Tsakonas S, Matsuno K, Fortini ME | title = Notch signaling | journal = Science | volume = 268 | issue = 5208 | pages = 225–232 | date = April 1995 | pmid = 7716513 | doi = 10.1126/science.7716513 | bibcode = 1995Sci...268..225A }} was found to be involved in the specification of cell fates during development in Drosophila and C. elegans.{{cite journal | vauthors = Singson A, Mercer KB, L'Hernault SW | title = The C. elegans spe-9 gene encodes a sperm transmembrane protein that contains EGF-like repeats and is required for fertilization | journal = Cell | volume = 93 | issue = 1 | pages = 71–79 | date = April 1998 | pmid = 9546393 | doi = 10.1016/S0092-8674(00)81147-2 | s2cid = 17455442 | doi-access = free }}

The intracellular domain of Notch forms a complex with CBF1 and Mastermind to activate transcription of target genes. The structure of the complex has been determined.{{cite journal | vauthors = Nam Y, Sliz P, Song L, Aster JC, Blacklow SC | title = Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes | journal = Cell | volume = 124 | issue = 5 | pages = 973–983 | date = March 2006 | pmid = 16530044 | doi = 10.1016/j.cell.2005.12.037 | s2cid = 17809522 | doi-access = free | author-link5 = Stephen Blacklow }}{{cite journal | vauthors = Wilson JJ, Kovall RA | title = Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA | journal = Cell | volume = 124 | issue = 5 | pages = 985–996 | date = March 2006 | pmid = 16530045 | doi = 10.1016/j.cell.2006.01.035 | s2cid = 9224353 | doi-access = free }}

Maturation of the notch receptor involves cleavage at the prospective extracellular side during intracellular trafficking in the Golgi complex.{{cite journal | vauthors = Munro S, Freeman M | title = The notch signalling regulator fringe acts in the Golgi apparatus and requires the glycosyltransferase signature motif DXD | journal = Current Biology | volume = 10 | issue = 14 | pages = 813–820 | date = July 2000 | pmid = 10899003 | doi = 10.1016/S0960-9822(00)00578-9 | s2cid = 13909969 | doi-access = free | bibcode = 2000CBio...10..813M }} This results in a bipartite protein, composed of a large extracellular domain linked to the smaller transmembrane and intracellular domain. Binding of ligand 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.

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.{{citation needed|date=May 2007}} The notch ligands are also single-pass transmembrane proteins and are members of the DSL (Delta/Serrate/LAG-2) family of proteins. In Drosophila melanogaster (the fruit fly), there are two ligands named Delta and Serrate. In mammals, the corresponding names are Delta-like and Jagged. In mammals there are multiple Delta-like and Jagged ligands, as well as possibly a variety of other ligands, such as F3/contactin.

In the nematode C. elegans, two genes encode homologous proteins, glp-1 and lin-12. 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.{{citation needed|date=June 2007}}

The notch extracellular domain is composed primarily of small cystine-rich motifs called EGF-like repeats.{{cite journal | vauthors = Ma B, Simala-Grant JL, Taylor DE | title = Fucosylation in prokaryotes and eukaryotes | journal = Glycobiology | volume = 16 | issue = 12 | pages = 158R–184R | date = December 2006 | pmid = 16973733 | doi = 10.1093/glycob/cwl040 | doi-access = }}

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 O-linked glycans at specific sites.{{cite journal | vauthors = Shao L, Luo Y, Moloney DJ, Haltiwanger R | title = O-glycosylation of EGF repeats: identification and initial characterization of a UDP-glucose: protein O-glucosyltransferase | journal = Glycobiology | volume = 12 | issue = 11 | pages = 763–770 | date = November 2002 | pmid = 12460944 | doi = 10.1093/glycob/cwf085 | doi-access = }} An O-glucose sugar may be added between the first and second conserved cysteines, and an O-fucose may be added between the second and third conserved cysteines. These sugars are added by an as-yet-unidentified O-glucosyltransferase (except for [https://www.ncbi.nlm.nih.gov/pubmed/18243100 Rumi]), and GDP-fucose Protein O-fucosyltransferase 1 (POFUT1), respectively. The addition of O-fucose by POFUT1 is absolutely necessary for notch function, and, without the enzyme to add O-fucose, all notch proteins fail to function properly. As yet, the manner by which the glycosylation of notch affects function is not completely understood.

The O-glucose on notch can be further elongated to a trisaccharide with the addition of two xylose sugars by xylosyltransferases, and the O-fucose can be elongated to a tetrasaccharide by the ordered addition of an N-acetylglucosamine (GlcNAc) sugar by an N-Acetylglucosaminyltransferase called Fringe, the addition of a galactose by a galactosyltransferase, and the addition of a sialic acid by a sialyltransferase.{{cite book | vauthors = Lu L, Stanley P | chapter = Roles of O-Fucose Glycans in Notch Signaling Revealed by Mutant Mice | title = Functional Glycomics | series = Methods in Enzymology | volume = 417 | pages = 127–136 | year = 2006 | pmid = 17132502 | doi = 10.1016/S0076-6879(06)17010-X | isbn = 9780121828226 }}

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.{{cite journal | vauthors = Thomas GB, van Meyel DJ | title = The glycosyltransferase Fringe promotes Delta-Notch signaling between neurons and glia, and is required for subtype-specific glial gene expression | journal = Development | volume = 134 | issue = 3 | pages = 591–600 | date = February 2007 | pmid = 17215308 | doi = 10.1242/dev.02754 | doi-access = free }} If Fringe adds a GlcNAc to the O-fucose 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.{{cite journal | vauthors = LaVoie MJ, Selkoe DJ | title = The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments | journal = The Journal of Biological Chemistry | volume = 278 | issue = 36 | pages = 34427–34437 | date = September 2003 | pmid = 12826675 | doi = 10.1074/jbc.M302659200 | doi-access = free }} The means by which this addition of sugar inhibits signaling through one ligand, and potentiates signaling through another is not clearly understood.

Once the notch extracellular domain interacts with a ligand, an ADAM-family metalloprotease called ADAM10, cleaves the notch protein just outside the membrane.{{cite journal | vauthors = van Tetering G, van Diest P, Verlaan I, van der Wall E, Kopan R, Vooijs M | title = Metalloprotease ADAM10 is required for Notch1 site 2 cleavage | journal = The Journal of Biological Chemistry | volume = 284 | issue = 45 | pages = 31018–31027 | date = November 2009 | pmid = 19726682 | pmc = 2781502 | doi = 10.1074/jbc.M109.006775 | doi-access = free }} This releases the extracellular portion of notch (NECD), which continues to interact with the ligand. The ligand plus the notch extracellular domain is then endocytosed 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.{{citation needed|reason=This claim needs a reliable source; Bogart was a famous actor, and his major biographies don't mention snooker.|date=August 2016}} After this first cleavage, an enzyme called γ-secretase (which is implicated in Alzheimer's disease) cleaves the remaining part of the notch protein just inside the inner leaflet of the cell membrane of the notch-expressing cell. This releases the intracellular domain of the notch protein (NICD), which then moves to the nucleus, where it can regulate gene expression by activating the transcription factor CSL. 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.{{cite book |doi=10.1038/npg.els.0004194 |chapter=Drosophila Patterning: Delta-Notch Interactions |title=Encyclopedia of Life Sciences |year=2006 | vauthors = Desbordes S, López-Schier H |isbn=0470016175 }} Other proteins also participate in the intracellular portion of the notch signaling cascade.{{cite journal | vauthors = Borggrefe T, Liefke R | title = Fine-tuning of the intracellular canonical Notch signaling pathway | journal = Cell Cycle | volume = 11 | issue = 2 | pages = 264–276 | date = January 2012 | pmid = 22223095 | doi = 10.4161/cc.11.2.18995 | doi-access = free }}

File:N1 dll4 cells.png

Notch signaling is initiated when Notch receptors on the cell surface engage ligands presented in trans on opposing cells. 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.{{cite journal | vauthors = Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S | title = Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor | journal = Cell | volume = 67 | issue = 4 | pages = 687–699 | date = November 1991 | pmid = 1657403 | doi = 10.1016/0092-8674(91)90064-6 | s2cid = 12643727 }} Additional studies have implicated regions outside of Notch EGF11-12 in ligand binding. For example, Notch EGF domain 8 plays a role in selective recognition of Serrate/Jagged{{cite journal | vauthors = Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S | title = Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor | journal = Cell | volume = 67 | issue = 4 | pages = 687–699 | date = November 1991 | pmid = 1657403 | doi = 10.1016/0092-8674(91)90064-6 | s2cid = 12643727 | bibcode = 2012Sci...338.1229Y }} and EGF domains 6-15 are required for maximal signaling upon ligand stimulation.{{Cite journal|date=2013|title=Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1|journal=Journal of Biological Chemistry}} 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.{{cite journal | vauthors = Luca VC, Jude KM, Pierce NW, Nachury MV, Fischer S, Garcia KC | title = Structural biology. Structural basis for Notch1 engagement of Delta-like 4 | journal = Science | volume = 347 | issue = 6224 | pages = 847–853 | date = February 2015 | pmid = 25700513 | pmc = 4445638 | doi = 10.1126/science.1261093 | bibcode = 2015Sci...347..847L }} 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.

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 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.{{cite journal | vauthors = Harmansa S, Affolter M | title = Protein binders and their applications in developmental biology | journal = Development | volume = 145 | issue = 2 | pages = dev148874 | date = January 2018 | pmid = 29374062 | doi = 10.1242/dev.148874 | doi-access = free }} Notably, this system allows multiple synthetic pathways to be engineered into a cell in parallel.{{cite journal | vauthors = Themeli M, Sadelain M | title = Combinatorial Antigen Targeting: Ideal T-Cell Sensing and Anti-Tumor Response | journal = Trends in Molecular Medicine | volume = 22 | issue = 4 | pages = 271–273 | date = April 2016 | pmid = 26971630 | pmc = 4994806 | doi = 10.1016/j.molmed.2016.02.009 }}{{cite journal | vauthors = Sadelain M | title = Chimeric antigen receptors: driving immunology towards synthetic biology | journal = Current Opinion in Immunology | volume = 41 | pages = 68–76 | date = August 2016 | pmid = 27372731 | pmc = 5520666 | doi = 10.1016/j.coi.2016.06.004 }}

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:

:* neuronal function and development{{cite journal | vauthors = Gaiano N, Fishell G | title = The role of notch in promoting glial and neural stem cell fates | journal = Annual Review of Neuroscience | volume = 25 | issue = 1 | pages = 471–490 | year = 2002 | pmid = 12052917 | doi = 10.1146/annurev.neuro.25.030702.130823 }}{{cite journal | vauthors = Bolós V, Grego-Bessa J, de la Pompa JL | title = Notch signaling in development and cancer | journal = Endocrine Reviews | volume = 28 | issue = 3 | pages = 339–363 | date = May 2007 | pmid = 17409286 | doi = 10.1210/er.2006-0046 | doi-access = free }}{{cite journal | vauthors = Aguirre A, Rubio ME, Gallo V | title = Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal | journal = Nature | volume = 467 | issue = 7313 | pages = 323–327 | date = September 2010 | pmid = 20844536 | pmc = 2941915 | doi = 10.1038/nature09347 | bibcode = 2010Natur.467..323A }}{{cite journal | vauthors = Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia AJ, Nye JS, Conlon RA, Mak TW, Bernstein A, van der Kooy D | display-authors = 6 | title = Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells | journal = Genes & Development | volume = 16 | issue = 7 | pages = 846–858 | date = April 2002 | pmid = 11937492 | pmc = 186324 | doi = 10.1101/gad.975202 }}

:* stabilization of arterial endothelial fate and angiogenesis{{cite journal | vauthors = Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, Fairman RM, Velazquez OC, Herlyn M | display-authors = 6 | title = Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis | journal = Molecular and Cellular Biology | volume = 23 | issue = 1 | pages = 14–25 | date = January 2003 | pmid = 12482957 | pmc = 140667 | doi = 10.1128/MCB.23.1.14-25.2003 }}

:* regulation of crucial cell communication events between endocardium and myocardium during both the formation of the valve primordial and ventricular development and differentiation{{cite journal | vauthors = Grego-Bessa J, Luna-Zurita L, del Monte G, Bolós V, Melgar P, Arandilla A, Garratt AN, Zang H, Mukouyama YS, Chen H, Shou W, Ballestar E, Esteller M, Rojas A, Pérez-Pomares JM, de la Pompa JL | display-authors = 6 | title = Notch signaling is essential for ventricular chamber development | journal = Developmental Cell | volume = 12 | issue = 3 | pages = 415–429 | date = March 2007 | pmid = 17336907 | pmc = 2746361 | doi = 10.1016/j.devcel.2006.12.011 }}

:* cardiac valve homeostasis, as well as implications in other human disorders involving the cardiovascular system[http://www.cnb.csic.es/groups-en/DIO/lineas_dpto5/jose_luis_de_la_pompa/index_html?set_language=en The notch signaling pathway in cardiac development and tissue homeostasis]{{Dead link|date=April 2020 |bot=InternetArchiveBot |fix-attempted=yes }}

:* timely cell lineage specification of both endocrine and exocrine pancreas{{cite journal | vauthors = Murtaugh LC, Stanger BZ, Kwan KM, Melton DA | title = Notch signaling controls multiple steps of pancreatic differentiation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 25 | pages = 14920–14925 | date = December 2003 | pmid = 14657333 | pmc = 299853 | doi = 10.1073/pnas.2436557100 | doi-access = free | bibcode = 2003PNAS..10014920M }}

:* influencing of binary fate decisions of cells that must choose between the secretory and absorptive lineages in the gut{{cite journal | vauthors = Sander GR, Powell BC | title = Expression of notch receptors and ligands in the adult gut | journal = The Journal of Histochemistry and Cytochemistry | volume = 52 | issue = 4 | pages = 509–516 | date = April 2004 | pmid = 15034002 | doi = 10.1177/002215540405200409 | doi-access = free }}

:* expansion of the hematopoietic stem cell compartment during bone development and participation in commitment to the osteoblastic lineage, suggesting a potential therapeutic role for notch in bone regeneration and osteoporosis{{cite journal | vauthors = Nobta M, Tsukazaki T, Shibata Y, Xin C, Moriishi T, Sakano S, Shindo H, Yamaguchi A | display-authors = 6 | title = Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling | journal = The Journal of Biological Chemistry | volume = 280 | issue = 16 | pages = 15842–15848 | date = April 2005 | pmid = 15695512 | doi = 10.1074/jbc.M412891200 | doi-access = free }}

:* expansion of the hemogenic endothelial cells along with signaling axis involving Hedgehog signaling and Scl{{cite journal | vauthors = Kim PG, Albacker CE, Lu YF, Jang IH, Lim Y, Heffner GC, Arora N, Bowman TV, Lin MI, Lensch MW, De Los Angeles A, Zon LI, Loewer S, Daley GQ | display-authors = 6 | title = Signaling axis involving Hedgehog, Notch, and Scl promotes the embryonic endothelial-to-hematopoietic transition | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 2 | pages = E141–E150 | date = January 2013 | pmid = 23236128 | pmc = 3545793 | doi = 10.1073/pnas.1214361110 | doi-access = free | bibcode = 2013PNAS..110E.141K }}

:*T cell lineage commitment from common lymphoid precursor {{cite journal | vauthors = Laky K, Fowlkes BJ | title = Notch signaling in CD4 and CD8 T cell development | journal = Current Opinion in Immunology | volume = 20 | issue = 2 | pages = 197–202 | date = April 2008 | pmid = 18434124 | pmc = 2475578 | doi = 10.1016/j.coi.2008.03.004 }}

:* regulation of cell-fate decision in mammary glands at several distinct development stages{{cite journal | vauthors = Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS | title = Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells | journal = Breast Cancer Research | volume = 6 | issue = 6 | pages = R605–R615 | year = 2004 | pmid = 15535842 | pmc = 1064073 | doi = 10.1186/bcr920 | doi-access = free }}

:* possibly some non-nuclear mechanisms, such as control of the actin cytoskeleton through the tyrosine kinase Abl{{cite journal | vauthors = Lai EC | title = Notch signaling: control of cell communication and cell fate | journal = Development | volume = 131 | issue = 5 | pages = 965–973 | date = March 2004 | pmid = 14973298 | doi = 10.1242/dev.01074 | s2cid = 6930563 | doi-access = }}

:* Regulation of the mitotic/meiotic decision in the C. elegans germline

:* development of alveoli in the lung.{{cite journal | vauthors = Guseh JS, Bores SA, Stanger BZ, Zhou Q, Anderson WJ, Melton DA, Rajagopal J | title = Notch signaling promotes airway mucous metaplasia and inhibits alveolar development | journal = Development | volume = 136 | issue = 10 | pages = 1751–1759 | date = May 2009 | pmid = 19369400 | pmc = 2673763 | doi = 10.1242/dev.029249 }}

It has also been found that Rex1 has inhibitory effects on the expression of notch in mesenchymal stem cells, preventing differentiation.{{cite journal | vauthors = Bhandari DR, Seo KW, Roh KH, Jung JW, Kang SK, Kang KS | title = REX-1 expression and p38 MAPK activation status can determine proliferation/differentiation fates in human mesenchymal stem cells | journal = PLOS ONE | volume = 5 | issue = 5 | pages = e10493 | date = May 2010 | pmid = 20463961 | pmc = 2864743 | doi = 10.1371/journal.pone.0010493 | veditors = Pera M | doi-access = free | bibcode = 2010PLoSO...510493B }}

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

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 somites.{{cite journal | vauthors = Feller J, Schneider A, Schuster-Gossler K, Gossler A | title = Noncyclic Notch activity in the presomitic mesoderm demonstrates uncoupling of somite compartmentalization and boundary formation | journal = Genes & Development | volume = 22 | issue = 16 | pages = 2166–2171 | date = August 2008 | pmid = 18708576 | pmc = 2518812 | doi = 10.1101/gad.480408 }} Also, Notch signaling is required during left-right asymmetry determination in vertebrates.{{cite journal | vauthors = Levin M | title = Left-right asymmetry in embryonic development: a comprehensive review | journal = Mechanisms of Development | volume = 122 | issue = 1 | pages = 3–25 | date = January 2005 | pmid = 15582774 | doi = 10.1016/j.mod.2004.08.006 | s2cid = 15211728 | doi-access = }}

Early studies in the nematode model organism C. elegans 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, glp-1 and lin-12.{{cite journal | vauthors = Lambie EJ, Kimble J | title = Two homologous regulatory genes, lin-12 and glp-1, have overlapping functions | journal = Development | volume = 112 | issue = 1 | pages = 231–240 | date = May 1991 | pmid = 1769331 | doi = 10.1242/dev.112.1.231 }} 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.{{cite book | title=Developmental biology| edition=11th| author=Gilbert SF| year=2016| pages=272| publisher=Sinauer| isbn=978-1-60535-470-5}}{{page needed|date=February 2020}}

{{anchor|Segmentation}}

Notch signaling is central to somitogenesis. In 1995, Notch1 was shown to be important for coordinating the segmentation of somites in mice.{{cite journal | vauthors = Conlon RA, Reaume AG, Rossant J | title = Notch1 is required for the coordinate segmentation of somites | journal = Development | volume = 121 | issue = 5 | pages = 1533–1545 | date = May 1995 | pmid = 7789282 | doi = 10.1242/dev.121.5.1533 }} 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.{{cite journal | vauthors = Hrabĕ de Angelis M, McIntyre J, Gossler A | title = Maintenance of somite borders in mice requires the Delta homologue DII1 | journal = Nature | volume = 386 | issue = 6626 | pages = 717–721 | date = April 1997 | pmid = 9109488 | doi = 10.1038/386717a0 | s2cid = 4331445 | bibcode = 1997Natur.386..717D }}{{cite journal | vauthors = van Eeden FJ, Granato M, Schach U, Brand M, Furutani-Seiki M, Haffter P, Hammerschmidt M, Heisenberg CP, Jiang YJ, Kane DA, Kelsh RN, Mullins MC, Odenthal J, Warga RM, Allende ML, Weinberg ES, Nüsslein-Volhard C | display-authors = 6 | title = Mutations affecting somite formation and patterning in the zebrafish, Danio rerio | journal = Development | volume = 123 | pages = 153–164 | date = December 1996 | pmid = 9007237 | doi = 10.1242/dev.123.1.153 }}{{cite journal | vauthors = Huppert SS, Ilagan MX, De Strooper B, Kopan R | title = Analysis of Notch function in presomitic mesoderm suggests a gamma-secretase-independent role for presenilins in somite differentiation | journal = Developmental Cell | volume = 8 | issue = 5 | pages = 677–688 | date = May 2005 | pmid = 15866159 | doi = 10.1016/j.devcel.2005.02.019 | doi-access = free }} 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.

During somitogenesis, a molecular oscillator in paraxial mesoderm cells dictates the precise rate of somite formation. A clock and wavefront model has been proposed in order to spatially determine the location and boundaries between somites. 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 spondylocostal dysostosis. 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.{{cite journal | vauthors = Wahi K, Bochter MS, Cole SE | title = The many roles of Notch signaling during vertebrate somitogenesis | journal = Seminars in Cell & Developmental Biology | volume = 49 | pages = 68–75 | date = January 2016 | pmid = 25483003 | doi = 10.1016/j.semcdb.2014.11.010 | s2cid = 10822545 }}

Notch signaling is known to occur inside ciliated, differentiating cells found in the first epidermal layers during early skin development.{{cite journal | vauthors = Lowell S, Jones P, Le Roux I, Dunne J, Watt FM | title = Stimulation of human epidermal differentiation by delta-notch signalling at the boundaries of stem-cell clusters | journal = Current Biology | volume = 10 | issue = 9 | pages = 491–500 | date = May 2000 | pmid = 10801437 | doi = 10.1016/s0960-9822(00)00451-6 | s2cid = 8927528 | doi-access = free | bibcode = 2000CBio...10..491L }} Furthermore, it has found that presenilin-2 works in conjunction with ARF4 to regulate Notch signaling during this development.{{cite journal | vauthors = Ezratty EJ, Pasolli HA, Fuchs E | title = A Presenilin-2-ARF4 trafficking axis modulates Notch signaling during epidermal differentiation | journal = The Journal of Cell Biology | volume = 214 | issue = 1 | pages = 89–101 | date = July 2016 | pmid = 27354375 | pmc = 4932368 | doi = 10.1083/jcb.201508082 }} However, it remains to be determined whether gamma-secretase has a direct or indirect role in modulating Notch signaling.

File:Neuro-Gliogenesis via Lateral Inhibition.png

Early findings on Notch signaling in central nervous system (CNS) development were performed mainly in Drosophila with mutagenesis experiments. For example, the finding that an embryonic lethal phenotype in Drosophila was associated with Notch dysfunction{{cite journal | vauthors = Poulson DF | title = Chromosomal Deficiencies and the Embryonic Development of Drosophila Melanogaster | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 23 | issue = 3 | pages = 133–137 | date = March 1937 | pmid = 16588136 | pmc = 1076884 | doi = 10.1073/pnas.23.3.133 | doi-access = free | bibcode = 1937PNAS...23..133P }} indicated that Notch mutations can lead to the failure of neural and Epidermal cell segregation in early Drosophila embryos. In the past decade, advances in mutation and knockout techniques allowed research on the Notch signaling pathway in mammalian models, especially rodents.

The Notch signaling pathway was found to be critical mainly for neural progenitor cell (NPC) maintenance and self-renewal. In recent years, other functions of the Notch pathway have also been found, including glial cell specification,{{cite journal | vauthors = Furukawa T, Mukherjee S, Bao ZZ, Morrow EM, Cepko CL | title = rax, Hes1, and notch1 promote the formation of Müller glia by postnatal retinal progenitor cells | journal = Neuron | volume = 26 | issue = 2 | pages = 383–394 | date = May 2000 | pmid = 10839357 | doi = 10.1016/S0896-6273(00)81171-X | s2cid = 16444353 | doi-access = free }}{{cite journal | vauthors = Scheer N, Groth A, Hans S, Campos-Ortega JA | title = An instructive function for Notch in promoting gliogenesis in the zebrafish retina | journal = Development | volume = 128 | issue = 7 | pages = 1099–1107 | date = April 2001 | pmid = 11245575 | doi = 10.1242/dev.128.7.1099 }} neurites development,{{cite journal | vauthors = Redmond L, Oh SR, Hicks C, Weinmaster G, Ghosh A | title = Nuclear Notch1 signaling and the regulation of dendritic development | journal = Nature Neuroscience | volume = 3 | issue = 1 | pages = 30–40 | date = January 2000 | pmid = 10607392 | doi = 10.1038/71104 | s2cid = 14774606 }} as well as learning and memory.{{cite journal | vauthors = Costa RM, Honjo T, Silva AJ | title = Learning and memory deficits in Notch mutant mice | journal = Current Biology | volume = 13 | issue = 15 | pages = 1348–1354 | date = August 2003 | pmid = 12906797 | doi = 10.1016/S0960-9822(03)00492-5 | s2cid = 15150614 | doi-access = free | bibcode = 2003CBio...13.1348C }}

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. Modulators of the Notch signal, e.g., the Numb protein are able to antagonize Notch effects, resulting in the halting of cell cycle and the differentiation of NPCs.{{cite journal | vauthors = Zhong W, Jiang MM, Weinmaster G, Jan LY, Jan YN | title = Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis | journal = Development | volume = 124 | issue = 10 | pages = 1887–1897 | date = May 1997 | pmid = 9169836 | doi = 10.1242/dev.124.10.1887 }}{{cite journal | vauthors = Li HS, Wang D, Shen Q, Schonemann MD, Gorski JA, Jones KR, Temple S, Jan LY, Jan YN | display-authors = 6 | title = Inactivation of Numb and Numblike in embryonic dorsal forebrain impairs neurogenesis and disrupts cortical morphogenesis | journal = Neuron | volume = 40 | issue = 6 | pages = 1105–1118 | date = December 2003 | pmid = 14687546 | doi = 10.1016/S0896-6273(03)00755-4 | s2cid = 6525042 | doi-access = free }} Conversely, the fibroblast growth factor pathway promotes Notch signaling to keep stem cells of the cerebral cortex in the proliferative state, amounting to a mechanism regulating cortical surface area growth and, potentially, gyrification.{{cite journal | vauthors = Rash BG, Lim HD, Breunig JJ, Vaccarino FM | title = FGF signaling expands embryonic cortical surface area by regulating Notch-dependent neurogenesis | journal = The Journal of Neuroscience | volume = 31 | issue = 43 | pages = 15604–15617 | date = October 2011 | pmid = 22031906 | pmc = 3235689 | doi = 10.1523/JNEUROSCI.4439-11.2011 }}{{cite journal | vauthors = Rash BG, Tomasi S, Lim HD, Suh CY, Vaccarino FM | title = Cortical gyrification induced by fibroblast growth factor 2 in the mouse brain | journal = The Journal of Neuroscience | volume = 33 | issue = 26 | pages = 10802–10814 | date = June 2013 | pmid = 23804101 | pmc = 3693057 | doi = 10.1523/JNEUROSCI.3621-12.2013 }} In this way, Notch signaling controls NPC self-renewal as well as cell fate specification.

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 (STAT3-Ser/Hes3 Signaling Axis) has been shown to regulate the number of NPCs in culture and in the adult rodent brain.{{cite journal | vauthors = Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R, McKay RD | display-authors = 6 | title = Notch signalling regulates stem cell numbers in vitro and in vivo | journal = Nature | volume = 442 | issue = 7104 | pages = 823–826 | date = August 2006 | pmid = 16799564 | doi = 10.1038/nature04940 | s2cid = 4372065 | bibcode = 2006Natur.442..823A | url = https://zenodo.org/record/1233295 }}

In adult rodents and in cell culture, Notch3 promotes neuronal differentiation, having a role opposite to Notch1/2.{{cite journal | vauthors = Rusanescu G, Mao J | title = Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord | journal = Journal of Cellular and Molecular Medicine | volume = 18 | issue = 10 | pages = 2103–2116 | date = October 2014 | pmid = 25164209 | pmc = 4244024 | doi = 10.1111/jcmm.12362 }} This indicates that individual Notch receptors can have divergent functions, depending on cellular context.

In vitro studies show that Notch can influence neurite development. In vivo, deletion of the Notch signaling modulator, Numb, disrupts neuronal maturation in the developing cerebellum,{{cite journal | vauthors = Klein AL, Zilian O, Suter U, Taylor V | title = Murine numb regulates granule cell maturation in the cerebellum | journal = Developmental Biology | volume = 266 | issue = 1 | pages = 161–177 | date = February 2004 | pmid = 14729486 | doi = 10.1016/j.ydbio.2003.10.017 | doi-access = free }} whereas deletion of Numb disrupts axonal arborization in sensory ganglia.{{cite journal | vauthors = Huang EJ, Li H, Tang AA, Wiggins AK, Neve RL, Zhong W, Jan LY, Jan YN | display-authors = 6 | title = Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborization | journal = Genes & Development | volume = 19 | issue = 1 | pages = 138–151 | date = January 2005 | pmid = 15598981 | pmc = 540232 | doi = 10.1101/gad.1246005 }} Although the mechanism underlying this phenomenon is not clear, together these findings suggest Notch signaling might be crucial in neuronal maturation.

In gliogenesis, Notch appears to have an instructive role that can directly promote the differentiation of many glial cell subtypes. For example, activation of Notch signaling in the retina favors the generation of Muller glia cells at the expense of neurons, whereas reduced Notch signaling induces production of ganglion cells, causing a reduction in the number of Muller glia.

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{{cite journal | vauthors = Woo HN, Park JS, Gwon AR, Arumugam TV, Jo DG | title = Alzheimer's disease and Notch signaling | journal = Biochemical and Biophysical Research Communications | volume = 390 | issue = 4 | pages = 1093–1097 | date = December 2009 | pmid = 19853579 | doi = 10.1016/j.bbrc.2009.10.093 }} In addition to developmental functions, Notch proteins and ligands are expressed in cells of the adult nervous system,{{cite journal | vauthors = Presente A, Andres A, Nye JS | title = Requirement of Notch in adulthood for neurological function and longevity | journal = NeuroReport | volume = 12 | issue = 15 | pages = 3321–3325 | date = October 2001 | pmid = 11711879 | doi = 10.1097/00001756-200110290-00035 | s2cid = 8329715 }} 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 presenilins1 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.{{cite journal | vauthors = Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, Chattarji S, Kelleher RJ, Kandel ER, Duff K, Kirkwood A, Shen J | display-authors = 6 | title = Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration | journal = Neuron | volume = 42 | issue = 1 | pages = 23–36 | date = April 2004 | pmid = 15066262 | doi = 10.1016/S0896-6273(04)00182-5 | s2cid = 17550860 | doi-access = free }} Several gamma secretase inhibitors that underwent human clinical trials in Alzheimer's disease and MCI patients resulted in statistically significant worsening of cognition relative to controls, which is thought to be due to its incidental effect on Notch signalling.{{cite journal | vauthors = De Strooper B | title = Lessons from a failed γ-secretase Alzheimer trial | journal = Cell | volume = 159 | issue = 4 | pages = 721–726 | date = November 2014 | pmid = 25417150 | doi = 10.1016/j.cell.2014.10.016 | doi-access = free }}

The Notch signaling pathway is a critical component of cardiovascular formation and morphogenesis in both development and disease. It is required for the selection of endothelial tip and stalk cells during sprouting angiogenesis.{{cite book | vauthors = Kume T | chapter = Ligand-Dependent Notch Signaling in Vascular Formation | series = Advances in Experimental Medicine and Biology | title = Notch Signaling in Embryology and Cancer | volume = 727 | pages = 210–222 | year = 2012 | pmid = 22399350 | doi = 10.1007/978-1-4614-0899-4_16 | isbn = 978-1-4614-0898-7 }}

Notch signal pathway plays a crucial role in at least three cardiac development processes: Atrioventricular canal development, myocardial development, and cardiac outflow tract (OFT) development.{{cite journal | vauthors = Niessen K, Karsan A | title = Notch signaling in cardiac development | journal = Circulation Research | volume = 102 | issue = 10 | pages = 1169–1181 | date = May 2008 | pmid = 18497317 | doi = 10.1161/CIRCRESAHA.108.174318 | doi-access = free }}

;AV boundary formation: Notch signaling can regulate the atrioventricular boundary formation between the AV canal and the chamber myocardium.
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 HEY1 and HEY2 are involved in restricting the expression of two critical developmental regulator proteins, BMP2 and Tbx2, to the AV canal.{{cite journal | vauthors = Rutenberg JB, Fischer A, Jia H, Gessler M, Zhong TP, Mercola M | title = Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors | journal = Development | volume = 133 | issue = 21 | pages = 4381–4390 | date = November 2006 | pmid = 17021042 | pmc = 3619037 | doi = 10.1242/dev.02607 }}{{cite journal | vauthors = Kokubo H, Tomita-Miyagawa S, Hamada Y, Saga Y | title = Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2 | journal = Development | volume = 134 | issue = 4 | pages = 747–755 | date = February 2007 | pmid = 17259303 | doi = 10.1242/dev.02777 | doi-access = free }}

;AV epithelial-mesenchymal transition (EMT): Notch signaling is also important for the process of AV EMT, 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 myocardium 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.{{cite journal | vauthors = Timmerman LA, Grego-Bessa J, Raya A, Bertrán E, Pérez-Pomares JM, Díez J, Aranda S, Palomo S, McCormick F, Izpisúa-Belmonte JC, de la Pompa JL | display-authors = 6 | title = Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation | journal = Genes & Development | volume = 18 | issue = 1 | pages = 99–115 | date = January 2004 | pmid = 14701881 | pmc = 314285 | doi = 10.1101/gad.276304 }} Notch may regulate this process by activating matrix metalloproteinase2 (MMP2) expression, or by inhibiting vascular endothelial (VE)-cadherin expression in the AV canal endocardium{{cite journal | vauthors = Crosby CV, Fleming PA, Argraves WS, Corada M, Zanetta L, Dejana E, Drake CJ | title = VE-cadherin is not required for the formation of nascent blood vessels but acts to prevent their disassembly | journal = Blood | volume = 105 | issue = 7 | pages = 2771–2776 | date = April 2005 | pmid = 15604224 | doi = 10.1182/blood-2004-06-2244 | doi-access = free }} while suppressing the VEGF pathway via VEGFR2.{{cite journal | vauthors = Noseda M, McLean G, Niessen K, Chang L, Pollet I, Montpetit R, Shahidi R, Dorovini-Zis K, Li L, Beckstead B, Durand RE, Hoodless PA, Karsan A | display-authors = 6 | title = Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation | journal = Circulation Research | volume = 94 | issue = 7 | pages = 910–917 | date = April 2004 | pmid = 14988227 | doi = 10.1161/01.RES.0000124300.76171.C9 | doi-access = free }} In RBPJk/CBF1-targeted mutants, the heart valve development is severely disrupted, presumably because of defective endocardial maturation and signaling.

Some studies in Xenopus{{cite journal | vauthors = Rones MS, McLaughlin KA, Raffin M, Mercola M | title = Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis | journal = Development | volume = 127 | issue = 17 | pages = 3865–3876 | date = September 2000 | pmid = 10934030 | doi = 10.1242/dev.127.17.3865 }} and in mouse embryonic stem cells{{cite journal | vauthors = Nemir M, Croquelois A, Pedrazzini T, Radtke F | title = Induction of cardiogenesis in embryonic stem cells via downregulation of Notch1 signaling | journal = Circulation Research | volume = 98 | issue = 12 | pages = 1471–1478 | date = June 2006 | pmid = 16690879 | doi = 10.1161/01.RES.0000226497.52052.2a | doi-access = free }} indicate that cardiomyogenic commitment and differentiation require Notch signaling inhibition. Active Notch signaling is required in the ventricular endocardium for proper trabeculae development subsequent to myocardial specification by regulating BMP10, NRG1, and EphrinB2 expression. Notch signaling sustains immature cardiomyocyte proliferation in mammals {{cite journal | vauthors = Croquelois A, Domenighetti AA, Nemir M, Lepore M, Rosenblatt-Velin N, Radtke F, Pedrazzini T | title = Control of the adaptive response of the heart to stress via the Notch1 receptor pathway | journal = The Journal of Experimental Medicine | volume = 205 | issue = 13 | pages = 3173–3185 | date = December 2008 | pmid = 19064701 | pmc = 2605223 | doi = 10.1084/jem.20081427 }}{{cite journal | vauthors = Collesi C, Zentilin L, Sinagra G, Giacca M | title = Notch1 signaling stimulates proliferation of immature cardiomyocytes | journal = The Journal of Cell Biology | volume = 183 | issue = 1 | pages = 117–128 | date = October 2008 | pmid = 18824567 | pmc = 2557047 | doi = 10.1083/jcb.200806091 }}{{cite journal | vauthors = Campa VM, Gutiérrez-Lanza R, Cerignoli F, Díaz-Trelles R, Nelson B, Tsuji T, Barcova M, Jiang W, Mercola M | display-authors = 6 | title = Notch activates cell cycle reentry and progression in quiescent cardiomyocytes | journal = The Journal of Cell Biology | volume = 183 | issue = 1 | pages = 129–141 | date = October 2008 | pmid = 18838555 | pmc = 2557048 | doi = 10.1083/jcb.200806104 }} and zebrafish.{{cite journal | vauthors = Zhao L, Borikova AL, Ben-Yair R, Guner-Ataman B, MacRae CA, Lee RT, Burns CG, Burns CE | display-authors = 6 | title = Notch signaling regulates cardiomyocyte proliferation during zebrafish heart regeneration | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 4 | pages = 1403–1408 | date = January 2014 | pmid = 24474765 | pmc = 3910613 | doi = 10.1073/pnas.1311705111 | doi-access = free | bibcode = 2014PNAS..111.1403Z }} A regulatory correspondence likely exists between Notch signaling and Wnt signaling, 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.{{cite web | vauthors = Teske CM |title=An Evolving Role for Notch Signaling in Heart Regeneration of the Zebrafish Danio rerio |url=https://www.researchgate.net/publication/362704455 |website=Researchgate.com |access-date=4 October 2022}}

The downstream effector of Notch signaling, HEY2, was also demonstrated to be important in regulating ventricular development by its expression in the interventricular septum and the endocardial cells of the cardiac cushions.{{cite journal | vauthors = Wang J, Sridurongrit S, Dudas M, Thomas P, Nagy A, Schneider MD, Epstein JA, Kaartinen V | display-authors = 6 | title = Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart | journal = Developmental Biology | volume = 286 | issue = 1 | pages = 299–310 | date = October 2005 | pmid = 16140292 | pmc = 1361261 | doi = 10.1016/j.ydbio.2005.07.035 }} Cardiomyocyte and smooth muscle cell-specific deletion of HEY2 results in impaired cardiac contractility, malformed right ventricle, and ventricular septal defects.{{cite journal | vauthors = Xin M, Small EM, van Rooij E, Qi X, Richardson JA, Srivastava D, Nakagawa O, Olson EN | display-authors = 6 | title = Essential roles of the bHLH transcription factor Hrt2 in repression of atrial gene expression and maintenance of postnatal cardiac function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 19 | pages = 7975–7980 | date = May 2007 | pmid = 17468400 | pmc = 1876557 | doi = 10.1073/pnas.0702447104 | doi-access = free | bibcode = 2007PNAS..104.7975X }}

During development of the aortic arch and the aortic arch arteries, the Notch receptors, ligands, and target genes display a unique expression pattern.{{cite journal | vauthors = High FA, Zhang M, Proweller A, Tu L, Parmacek MS, Pear WS, Epstein JA | title = An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation | journal = The Journal of Clinical Investigation | volume = 117 | issue = 2 | pages = 353–363 | date = February 2007 | pmid = 17273555 | pmc = 1783803 | doi = 10.1172/JCI30070 }} When the Notch pathway was blocked, the induction of vascular smooth muscle 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.

Endothelial cells use the Notch signaling pathway to coordinate cellular behaviors during the blood vessel sprouting that occurs sprouting angiogenesis.{{cite journal | vauthors = Hellström M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalén M, Gerhardt H, Betsholtz C | display-authors = 6 | title = Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis | journal = Nature | volume = 445 | issue = 7129 | pages = 776–780 | date = February 2007 | pmid = 17259973 | doi = 10.1038/nature05571 | s2cid = 4407198 | bibcode = 2007Natur.445..776H }}{{cite journal | vauthors = Leslie JD, Ariza-McNaughton L, Bermange AL, McAdow R, Johnson SL, Lewis J | title = Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis | journal = Development | volume = 134 | issue = 5 | pages = 839–844 | date = March 2007 | pmid = 17251261 | doi = 10.1242/dev.003244 | doi-access = free }}{{cite journal | vauthors = Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, Wiegand SJ | title = Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 9 | pages = 3219–3224 | date = February 2007 | pmid = 17296940 | pmc = 1805530 | doi = 10.1073/pnas.0611206104 | doi-access = free | bibcode = 2007PNAS..104.3219L }}{{cite journal | vauthors = Siekmann AF, Lawson ND | title = Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries | journal = Nature | volume = 445 | issue = 7129 | pages = 781–784 | date = February 2007 | pmid = 17259972 | doi = 10.1038/nature05577 | s2cid = 4349541 | bibcode = 2007Natur.445..781S }}

Activation of Notch takes place primarily in "connector" cells and cells that line patent stable blood vessels through direct interaction with the Notch ligand, Delta-like ligand 4 (Dll4), which is expressed in the endothelial tip cells.{{cite journal | vauthors = Siekmann AF, Lawson ND | title = Notch signalling and the regulation of angiogenesis | journal = Cell Adhesion & Migration | volume = 1 | issue = 2 | pages = 104–106 | year = 2007 | pmid = 19329884 | pmc = 2633979 | doi = 10.4161/cam.1.2.4488 }} VEGF signaling, which is an important factor for migration and proliferation of endothelial cells,{{cite journal | vauthors = Zachary I, Gliki G | title = Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family | journal = Cardiovascular Research | volume = 49 | issue = 3 | pages = 568–581 | date = February 2001 | pmid = 11166270 | doi = 10.1016/S0008-6363(00)00268-6 | doi-access = free }} can be downregulated in cells with activated Notch signaling by lowering the levels of Vegf receptor transcript.{{cite journal | vauthors = Williams CK, Li JL, Murga M, Harris AL, Tosato G | title = Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function | journal = Blood | volume = 107 | issue = 3 | pages = 931–939 | date = February 2006 | pmid = 16219802 | pmc = 1895896 | doi = 10.1182/blood-2005-03-1000 }} 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.{{cite journal | vauthors = Lawson ND, Scheer N, Pham VN, Kim CH, Chitnis AB, Campos-Ortega JA, Weinstein BM | title = Notch signaling is required for arterial-venous differentiation during embryonic vascular development | journal = Development | volume = 128 | issue = 19 | pages = 3675–3683 | date = October 2001 | pmid = 11585794 | doi = 10.1242/dev.128.19.3675 }}

Notch signaling may be used to control the sprouting pattern of blood vessels during angiogenesis. When cells within a patent vessel are exposed to VEGF signaling, only a restricted number of them initiate the angiogenic process. Vegf is able to induce DLL4 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 patent connection to the original blood vessel.

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

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.{{cite journal | vauthors = Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, Hrabe de Angelis M, Lendahl U, Edlund H | display-authors = 6 | title = Notch signalling controls pancreatic cell differentiation | journal = Nature | volume = 400 | issue = 6747 | pages = 877–881 | date = August 1999 | pmid = 10476967 | doi = 10.1038/23716 | s2cid = 4338027 | bibcode = 1999Natur.400..877A }}{{cite journal | vauthors = Lammert E, Brown J, Melton DA | title = Notch gene expression during pancreatic organogenesis | journal = Mechanisms of Development | volume = 94 | issue = 1–2 | pages = 199–203 | date = June 2000 | pmid = 10842072 | doi = 10.1016/S0925-4773(00)00317-8 | s2cid = 9931966 | doi-access = }} Evidence suggests Notch signaling regulates the progressive recruitment of endocrine cell types from a common precursor,{{cite journal | vauthors = Field HA, Dong PD, Beis D, Stainier DY | title = Formation of the digestive system in zebrafish. II. Pancreas morphogenesis | journal = Developmental Biology | volume = 261 | issue = 1 | pages = 197–208 | date = September 2003 | pmid = 12941629 | doi = 10.1016/S0012-1606(03)00308-7 | doi-access = }} 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.{{cite journal | vauthors = Jensen J, Pedersen EE, Galante P, Hald J, Heller RS, Ishibashi M, Kageyama R, Guillemot F, Serup P, Madsen OD | display-authors = 6 | title = Control of endodermal endocrine development by Hes-1 | journal = Nature Genetics | volume = 24 | issue = 1 | pages = 36–44 | date = January 2000 | pmid = 10615124 | doi = 10.1038/71657 | s2cid = 52872659 }} 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.{{cite journal | vauthors = Jensen J | title = Gene regulatory factors in pancreatic development | journal = Developmental Dynamics | volume = 229 | issue = 1 | pages = 176–200 | date = January 2004 | pmid = 14699589 | doi = 10.1002/dvdy.10460 | doi-access = free }}{{cite journal | vauthors = Norgaard GA, Jensen JN, Jensen J | title = FGF10 signaling maintains the pancreatic progenitor cell state revealing a novel role of Notch in organ development | journal = Developmental Biology | volume = 264 | issue = 2 | pages = 323–338 | date = December 2003 | pmid = 14651921 | doi = 10.1016/j.ydbio.2003.08.013 | title-link = Pancreatic Progenitor Cell | doi-access = free }}

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.{{cite journal | vauthors = Crosnier C, Vargesson N, Gschmeissner S, Ariza-McNaughton L, Morrison A, Lewis J | title = Delta-Notch signalling controls commitment to a secretory fate in the zebrafish intestine | journal = Development | volume = 132 | issue = 5 | pages = 1093–1104 | date = March 2005 | pmid = 15689380 | doi = 10.1242/dev.01644 | doi-access = free }} Transcriptional analysis and gain of function experiments revealed that Notch signaling targets Hes1 in the intestine and regulates a binary cell fate decision between adsorptive and secretory cell fates.

Early in vitro studies have found the Notch signaling pathway functions as down-regulator in osteoclastogenesis and osteoblastogenesis.{{cite journal | vauthors = Yamada T, Yamazaki H, Yamane T, Yoshino M, Okuyama H, Tsuneto M, Kurino T, Hayashi S, Sakano S | display-authors = 6 | title = Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells | journal = Blood | volume = 101 | issue = 6 | pages = 2227–2234 | date = March 2003 | pmid = 12411305 | doi = 10.1182/blood-2002-06-1740 | doi-access = free }} Notch1 is expressed in the mesenchymal condensation area and subsequently in the hypertrophic chondrocytes during chondrogenesis.{{cite journal | vauthors = Watanabe N, Tezuka Y, Matsuno K, Miyatani S, Morimura N, Yasuda M, Fujimaki R, Kuroda K, Hiraki Y, Hozumi N, Tezuka K | display-authors = 6 | title = Suppression of differentiation and proliferation of early chondrogenic cells by Notch | journal = Journal of Bone and Mineral Metabolism | volume = 21 | issue = 6 | pages = 344–352 | year = 2003 | pmid = 14586790 | doi = 10.1007/s00774-003-0428-4 | s2cid = 1881239 }} 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 regeneration.

Notch signaling is critical for cell fate identity and differentiation and regulates these processes in part by controlling cell cycle progression. Specifically, Notch has been shown to promote cell cycle progression at the G1/S transition in various systems.

In Drosophila eye development, photoreceptors undergo two waves of differentiation, where five out of eight photoreceptors differentiate in the first wave (R8, R2, R5, R3, and R4), and the other three differentiate in the second wave (R1, R6, and R7).{{Cite journal |last=Treisman |first=Jessica E. |date=July 2013 |title=Retinal differentiation in Drosophila |journal=WIREs Developmental Biology |language=en |volume=2 |issue=4 |pages=545–557 |doi=10.1002/wdev.100 |issn=1759-7684 |pmc=3909661 |pmid=24014422}} Notch has been shown to promote the second mitotic wave in Drosophila eye development.{{Cite journal |last1=Baonza |first1=Antonio |last2=Freeman |first2=Matthew |date=2005-04-01 |title=Control of Cell Proliferation in the Drosophila Eye by Notch Signaling |url=https://linkinghub.elsevier.com/retrieve/pii/S1534580705000237 |journal=Developmental Cell |language=English |volume=8 |issue=4 |pages=529–539 |doi=10.1016/j.devcel.2005.01.019 |issn=1534-5807 |pmid=15809035}} Specifically, it mediates the G1/S transition by promoting dE2F activation (Drosophila E2F), a member of the E2F transcription factor family, which regulates the expression of genes important for cell proliferation, specifically those involved in the G1/S transition.{{Cite journal |last1=Johnson |first1=David G. |last2=Schneider-Broussard |first2=Robin |date=1998-04-27 |title=Role of E2F in cell cycle control and cancer |url=https://www.imrpress.com/journal/FBL/3/4/10.2741/A291 |journal=Frontiers in Bioscience (Landmark Edition) |volume=3 |issue=4 |pages=447–458 |doi=10.2741/A291 |pmid=9556498 |issn=2768-6701}} Notch does this by inhibiting RBF1 (the Drosophila homolog of the tumor suppressor Rb), which represses dE2F. Additionally, Notch is required for cyclin A activation, which accumulates during the G1/S transition and may be involved in S phase onset.

The role of Notch signaling in cell cycle regulation also has implications in health and disease. For example, Notch has been found to promote the expression of cyclin D3 and Cdk4/6 in human T-cells, thereby promoting the phosphorylation of Rb and facilitating the G1/S transition, implicating its role in cancer as several gain-of-function mutations in NOTCH1 have been identified in human acute T-cell lymphoblastic leukemias and lymphomas.{{Cite journal |last1=Joshi |first1=Ila |last2=Minter |first2=Lisa M. |last3=Telfer |first3=Janice |last4=Demarest |first4=Renée M. |last5=Capobianco |first5=Anthony J. |last6=Aster |first6=Jon C. |last7=Sicinski |first7=Piotr |last8=Fauq |first8=Abdul |last9=Golde |first9=Todd E. |last10=Osborne |first10=Barbara A. |date=2009-02-19 |title=Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases |url=https://ashpublications.org/blood/article/113/8/1689/26066/Notch-signaling-mediates-G1S-cellcycle-progression |journal=Blood |language=en |volume=113 |issue=8 |pages=1689–1698 |doi=10.1182/blood-2008-03-147967 |issn=0006-4971 |pmc=2647664 |pmid=19001083}}{{Cite journal |last=Aster |first=Jon C. |date=2005-11-01 |title=Deregulated NOTCH Signaling in Acute T-Cell Lymphoblastic Leukemia/Lymphoma: New Insights, Questions, and Opportunities |url=https://link.springer.com/article/10.1532/IJH97.05096 |journal=International Journal of Hematology |language=en |volume=82 |issue=4 |pages=295–301 |doi=10.1532/IJH97.05096 |pmid=16298817 |issn=1865-3774}} Additionally, in ventricular cardiomyocytes, which stop dividing shortly after birth, NOTCH2 signaling activation promotes cell cycle reentry. It induces the expression and nuclear translocation of cyclin D, which along with Cdk4/6 promotes the phosphorylation of Rb and causes cell cycle progression through the G1/S transition. This suggests that Notch signaling might regulate ventricular growth as well as cardiomyocyte regeneration, though this is unclear.

In the zebrafish trunk neural crest (TNC), cells migrate collectively in single-file chains, with a cell “leader” at the front of the chain that instructs the directionality of the trailing “follower” cells.{{Cite journal |last1=Richardson |first1=Jo |last2=Gauert |first2=Anton |last3=Briones Montecinos |first3=Luis |last4=Fanlo |first4=Lucía |last5=Alhashem |first5=Zainalabdeen Mohmammed |last6=Assar |first6=Rodrigo |last7=Marti |first7=Elisa |last8=Kabla |first8=Alexandre |last9=Härtel |first9=Steffen |last10=Linker |first10=Claudia |date=2016-05-31 |title=Leader Cells Define Directionality of Trunk, but Not Cranial, Neural Crest Cell Migration |journal=Cell Reports |language=English |volume=15 |issue=9 |pages=2076–2088 |doi=10.1016/j.celrep.2016.04.067 |issn=2211-1247 |pmc=4893160 |pmid=27210753}} Notch has been found to specify cell migratory identity in the trunk neural crest – specifically, high Notch specifies leaders while low Notch specifies followers.{{Cite journal |last1=Alhashem |first1=Zain |last2=Feldner-Busztin |first2=Dylan |last3=Revell |first3=Christopher |last4=Alvarez-Garcillan Portillo |first4=Macarena |last5=Camargo-Sosa |first5=Karen |last6=Richardson |first6=Joanna |last7=Rocha |first7=Manuel |last8=Gauert |first8=Anton |last9=Corbeaux |first9=Tatianna |last10=Milanetto |first10=Martina |last11=Argenton |first11=Francesco |last12=Tiso |first12=Natascia |last13=Kelsh |first13=Robert N |last14=Prince |first14=Victoria E |last15=Bentley |first15=Katie |date=2022-04-19 |editor-last=Piotrowski |editor-first=Tatjana |editor2-last=White |editor2-first=Richard M |title=Notch controls the cell cycle to define leader versus follower identities during collective cell migration |journal=eLife |volume=11 |pages=e73550 |doi=10.7554/eLife.73550 |doi-access=free |issn=2050-084X |pmc=9129880 |pmid=35438077}} Further, cell cycle progression required for migration is regulated by Notch such that leader cells with high Notch activity quickly undergo the G1/S transition while cells with low Notch activity remain in the G1 phase for longer and thus become followers.

Aberrant Notch signaling is a driver of T cell acute lymphoblastic leukemia (T-ALL){{cite journal | vauthors = Göthert JR, Brake RL, Smeets M, Dührsen U, Begley CG, Izon DJ | title = NOTCH1 pathway activation is an early hallmark of SCL T leukemogenesis | journal = Blood | volume = 110 | issue = 10 | pages = 3753–3762 | date = November 2007 | pmid = 17698635 | doi = 10.1182/blood-2006-12-063644 | doi-access = free }} and is mutated in at least 65% of all T-ALL cases.{{cite journal | vauthors = Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC | display-authors = 6 | title = Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia | journal = Science | volume = 306 | issue = 5694 | pages = 269–271 | date = October 2004 | pmid = 15472075 | doi = 10.1126/science.1102160 | s2cid = 24049536 | citeseerx = 10.1.1.459.5126 | bibcode = 2004Sci...306..269W }} Notch signaling can be activated by mutations in Notch itself, inactivating mutations in FBXW7 (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 c-MYC to activate anabolic pathways such as ribosome and protein biosynthesis thereby promoting leukemia cell growth.{{cite journal | vauthors = Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A, Barnes KC, O'Neil J, Neuberg D, Weng AP, Aster JC, Sigaux F, Soulier J, Look AT, Young RA, Califano A, Ferrando AA | display-authors = 6 | title = NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 48 | pages = 18261–18266 | date = November 2006 | pmid = 17114293 | pmc = 1838740 | doi = 10.1073/pnas.0606108103 | doi-access = free | bibcode = 2006PNAS..10318261P }}

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 tumorigenesis in the urinary tract.{{cite journal | vauthors = Rampias T, Vgenopoulou P, Avgeris M, Polyzos A, Stravodimos K, Valavanis C, Scorilas A, Klinakis A | display-authors = 6 | title = A new tumor suppressor role for the Notch pathway in bladder cancer | journal = Nature Medicine | volume = 20 | issue = 10 | pages = 1199–1205 | date = October 2014 | pmid = 25194568 | doi = 10.1038/nm.3678 | s2cid = 5390234 }} 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.{{cite journal | vauthors = Ristic Petrovic A, Stokanović D, Stojnev S, Potić Floranović M, Krstić M, Djordjević I, Skakić A, Janković Veličković L | display-authors = 6 | title = The association between NOTCH3 expression and the clinical outcome in the urothelial bladder cancer patients | journal = Bosnian Journal of Basic Medical Sciences | volume = 22 | issue = 4 | pages = 523–530 | date = July 2022 | pmid = 35073251 | pmc = 9392971 | doi = 10.17305/bjbms.2021.6767 }}

In hepatocellular carcinoma, for instance, it was suggesting that AXIN1 mutations would provoke Notch signaling pathway activation, fostering the cancer development, but a recent study demonstrated that such an effect cannot be detected. {{cite journal | vauthors = Zhang R, Li S, Schippers K, Eimers B, Niu J, Hornung BV, van den Hout MC, van Ijcken WF, Peppelenbosch MP, Smits R| title = Unraveling the impact of AXIN1 mutations on HCC development: Insights from CRISPR/Cas9 repaired AXIN1-mutant liver cancer cell lines. | journal = PLOS ONE | volume = 19 | issue = 6 | pages = e0304607| date = June 2024 | pmid = 38848383 | pmc = 11161089 | doi = 10.1371/journal.pone.0304607 | doi-access = free| bibcode = 2024PLoSO..1904607Z }} Thus the exact role of Notch signaling in the cancer process awaits further elucidation.

{{see also|DAPT (chemical)}}

The involvement of Notch signaling in many cancers has led to investigation of notch inhibitors (especially gamma-secretase inhibitors) as cancer treatments which are in different phases of clinical trials.{{cite book | vauthors = Purow B | chapter = Notch Inhibition as a Promising New Approach to Cancer Therapy | series = Advances in Experimental Medicine and Biology | title = Notch Signaling in Embryology and Cancer | volume = 727 | pages = 305–319 | year = 2012 | pmid = 22399357 | pmc = 3361718 | doi = 10.1007/978-1-4614-0899-4_23 | isbn = 978-1-4614-0898-7 }} {{as of |2013}} at least 7 notch inhibitors were in clinical trials.{{cite journal | vauthors = Espinoza I, Miele L | title = Notch inhibitors for cancer treatment | journal = Pharmacology & Therapeutics | volume = 139 | issue = 2 | pages = 95–110 | date = August 2013 | pmid = 23458608 | pmc = 3732476 | doi = 10.1016/j.pharmthera.2013.02.003 }} MK-0752 has given promising results in an early clinical trial for breast cancer.{{cite web |url=https://oncology-central.com/content/news/notch-inhibitors-could-help-overcome-therapy-resistance-in-er-positive-breast-cancer |title=Notch inhibitors could help overcome therapy resistance in ER-positive breast cancer |year=2015 |access-date=2015-02-05 |archive-date=2015-02-05 |archive-url=https://web.archive.org/web/20150205035222/https://oncology-central.com/content/news/notch-inhibitors-could-help-overcome-therapy-resistance-in-er-positive-breast-cancer |url-status=dead }} Preclinical studies showed beneficial effects of gamma-secretase inhibitors in endometriosis,{{cite journal | vauthors = Ramirez Williams L, Brüggemann K, Hubert M, Achmad N, Kiesel L, Schäfer SD, Greve B, Götte M | display-authors = 6 | title = γ-Secretase inhibition affects viability, apoptosis, and the stem cell phenotype of endometriotic cells | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 98 | issue = 12 | pages = 1565–1574 | date = December 2019 | pmid = 31424097 | doi = 10.1111/aogs.13707 | doi-access = free }} a disease characterised by increased expression of notch pathway constituents.{{cite journal | vauthors = Schüring AN, Dahlhues B, Korte A, Kiesel L, Titze U, Heitkötter B, Ruckert C, Götte M | display-authors = 6 | title = The endometrial stem cell markers notch-1 and numb are associated with endometriosis | journal = Reproductive Biomedicine Online | volume = 36 | issue = 3 | pages = 294–301 | date = March 2018 | pmid = 29398419 | doi = 10.1016/j.rbmo.2017.11.010 | s2cid = 4912558 | url = https://zenodo.org/record/3695800 }}{{cite journal | vauthors = Götte M, Wolf M, Staebler A, Buchweitz O, Kelsch R, Schüring AN, Kiesel L | title = Increased expression of the adult stem cell marker Musashi-1 in endometriosis and endometrial carcinoma | journal = The Journal of Pathology | volume = 215 | issue = 3 | pages = 317–329 | date = July 2008 | pmid = 18473332 | doi = 10.1002/path.2364 | s2cid = 206323361 }} Several notch inhibitors, including the gamma-secretase inhibitor LY3056480, are being studied for their potential ability to regenerate hair cells in the cochlea, which could lead to treatments for hearing loss and tinnitus.{{cite journal | vauthors = Erni ST, Gill JC, Palaferri C, Fernandes G, Buri M, Lazarides K, Grandgirard D, Edge AS, Leib SL, Roccio M | display-authors = 6 | title = Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors | journal = Frontiers in Cell and Developmental Biology | volume = 9 | pages = 710159 | date = 13 August 2021 | pmid = 34485296 | pmc = 8414802 | doi = 10.3389/fcell.2021.710159 | publisher = Frontiers Media SA | doi-access = free }}{{cite journal | vauthors = Samarajeewa A, Jacques BE, Dabdoub A | title = Therapeutic Potential of Wnt and Notch Signaling and Epigenetic Regulation in Mammalian Sensory Hair Cell Regeneration | journal = Molecular Therapy | volume = 27 | issue = 5 | pages = 904–911 | date = May 2019 | pmid = 30982678 | pmc = 6520458 | doi = 10.1016/j.ymthe.2019.03.017 | publisher = Elsevier BV }}

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,{{cite journal | vauthors = Collier JR, Monk NA, Maini PK, Lewis JH | title = Pattern formation by lateral inhibition with feedback: a mathematical model of delta-notch intercellular signalling | journal = Journal of Theoretical Biology | volume = 183 | issue = 4 | pages = 429–446 | date = December 1996 | pmid = 9015458 | doi = 10.1006/jtbi.1996.0233 | bibcode = 1996JThBi.183..429C | url = https://ora.ox.ac.uk/objects/uuid:d18e2570-90fd-47d5-94ad-3a4df1c0fe4c }} a cornerstone in this field, employs a system of coupled ordinary differential equations to describe the feedback loop between adjacent cells. The model is defined by the equations:$$\backslash begin\{align\}$$

\frac{d}{dt}n_i &= f(\langle d_i\rangle) - n_i \\

\frac{d}{dt}d_i &= \nu(g(n_i) - d_i)

\end{align}

where $n\_i$ and $d\_i$ represent the levels of Notch and Delta activity in cell $i$, respectively. Functions $f$ and $g$ are typically Hill functions, reflecting the regulatory dynamics of the signaling process. The term $\backslash langle\; d\_i\backslash rangle$ denotes the average level of Delta activity in the cells adjacent to cell $i$, integrating juxtacrine signaling effects.

Recent extensions of this model incorporate long-range signaling, acknowledging the role of cell protrusions like filopodia (cytonemes) that reach non-neighboring cells.{{cite journal | vauthors = Berkemeier F, Page KM | title = Coupling dynamics of 2D Notch-Delta signalling | journal = Mathematical Biosciences | volume = 360 | pages = 109012 | date = June 2023 | pmid = 37142213 | doi = 10.1016/j.mbs.2023.109012 | doi-access = free }}{{cite journal | vauthors = Vasilopoulos G, Painter KJ | title = Pattern formation in discrete cell tissues under long range filopodia-based direct cell to cell contact | journal = Mathematical Biosciences | volume = 273 | pages = 1–15 | date = March 2016 | pmid = 26748293 | doi = 10.1016/j.mbs.2015.12.008 }}{{Cite web | vauthors = Eisen JS |date=2010-07-27 |title=Faculty Opinions recommendation of Dynamic filopodia transmit intermittent Delta-Notch signaling to drive pattern refinement during lateral inhibition. |doi=10.3410/f.4361976.4187082 |doi-access=free }}{{cite journal | vauthors = Cohen M, Baum B, Miodownik M | title = The importance of structured noise in the generation of self-organizing tissue patterns through contact-mediated cell-cell signalling | journal = Journal of the Royal Society, Interface | volume = 8 | issue = 59 | pages = 787–798 | date = June 2011 | pmid = 21084342 | pmc = 3104346 | doi = 10.1098/rsif.2010.0488 }} One extended model, often referred to as the $\backslash epsilon$-Collier model, introduces a weighting parameter $\backslash epsilon\; \backslash in\; [0,1]$ to balance juxtacrine and long-range signaling. The interaction term $\backslash langle\; d\_i\backslash rangle$ 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 mathematical modeling in Notch-Delta signaling has been particularly illuminating in understanding the patterning of sensory organ precursors (SOPs) in the Drosophila's notum and wing margin.{{cite book | vauthors = Binshtok U, Sprinzak D | chapter = Modeling the Notch Response | title = Molecular Mechanisms of Notch Signaling | volume = 1066 | pages = 79–98 | date = 2018 | pmid = 30030823 | pmc = 6879322 | doi = 10.1007/978-3-319-89512-3_5 | isbn = 978-3-319-89512-3 | series = Advances in Experimental Medicine and Biology | veditors = Borggrefe T, Giaimo B | publisher = Springer International Publishing | place = Cham }}{{cite journal | vauthors = Hunter GL, Hadjivasiliou Z, Bonin H, He L, Perrimon N, Charras G, Baum B | title = Coordinated control of Notch/Delta signalling and cell cycle progression drives lateral inhibition-mediated tissue patterning | journal = Development | volume = 143 | issue = 13 | pages = 2305–2310 | date = July 2016 | pmid = 27226324 | pmc = 4958321 | doi = 10.1242/dev.134213 }}

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

• Alagille syndrome
• Netpath – A curated resource of signal transduction pathways in humans

{{Reflist|33em}}

• Diagram: [https://web.archive.org/web/20070929120458/http://www.genome.jp/dbget-bin/get_pathway?org_name=hsa&mapno=04330 notch signaling pathway in Homo sapiens]
• Diagram: [http://www.genome.jp/kegg/pathway/dme/dme04330.html Notch signaling in Drosophila] {{Webarchive|url=https://web.archive.org/web/20171109152324/http://www.genome.jp/kegg/pathway/dme/dme04330.html |date=2017-11-09 }}
• {{MeshName|Notch+Receptors}}

{{Cell signaling}}

{{Notch signaling pathway}}

{{genarch}}

Category:Signal transduction