Editing Notch signaling pathway (section)

=== Neuron cell differentiation ===

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.<ref name="pmid17409286" /> Modulators of the Notch signal, e.g., the [[NUMB (gene)|Numb]] protein are able to antagonize Notch effects, resulting in the halting of cell cycle and the differentiation of NPCs.<ref>{{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 }}</ref><ref>{{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 }}</ref> Conversely, the [[fibroblast growth factor]] pathway promotes Notch signaling to keep [[stem cell]]s of the [[cerebral cortex]] in the proliferative state, amounting to a mechanism regulating cortical surface area growth and, potentially, [[gyrification]].<ref>{{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 }}</ref><ref>{{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 }}</ref> 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 ([[Hes3 signaling axis|STAT3-Ser/Hes3 Signaling Axis]]) has been shown to regulate the number of NPCs in culture and in the adult rodent brain.<ref>{{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 }}</ref>

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