Editing Notch signaling pathway (section)

== Role in embryogenesis ==

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

=== Embryo polarity ===

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]].<ref>{{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 }}</ref> Also, Notch signaling is required during left-right asymmetry determination in vertebrates.<ref>{{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 =  }}</ref>

Early studies in the [[nematode]] model organism [[Caenorhabditis elegans|''C. elegans'']] indicate that Notch signaling has a major role in the induction of mesoderm and cell fate determination.<ref name=pmid3677168/> As mentioned previously, C. elegans has two genes that encode for partially functionally redundant Notch homologs, ''glp-1'' and ''lin-12''.<ref>{{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 }}</ref> 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.<ref>{{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}}</ref>

=== Role in somitogenesis ===
{{anchor|Segmentation}}

Notch signaling is central to [[somitogenesis]]. In 1995, Notch1 was shown to be important for coordinating the segmentation of somites in mice.<ref name="Conlon RA, Reaume AG, Rossant J 1995 1533–45">{{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 }}</ref> 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.<ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref> 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.<ref name="Conlon RA, Reaume AG, Rossant J 1995 1533–45" />

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.<ref>{{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 }}</ref>

=== Role in epidermal differentiation ===
Notch signaling is known to occur inside ciliated, differentiating cells found in the first epidermal layers during early skin development.<ref>{{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 }}</ref> Furthermore, it has found that [[PSEN2|presenilin-2]] works in conjunction with ARF4 to regulate Notch signaling during this development.<ref>{{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 }}</ref> However, it remains to be determined whether gamma-secretase has a direct or indirect role in modulating Notch signaling.