Notch Signaling and Embryonic Development: An Ancient Friend, Revisited

  • Jörg ReichrathEmail author
  • Sandra Reichrath
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1218)


The evolutionary highly conserved Notch pathway, which first developed during evolution in metazoans and was first discovered in fruit flies (Drosophila melanogaster), governs many core processes including cell fate decisions during embryonic development. A huge mountain of scientific evidence convincingly demonstrates that Notch signaling represents one of the most important pathways that regulate embryogenesis from sponges, roundworms, Drosophila melanogaster, and mice to humans. In this review, we give a brief introduction on how Notch orchestrates the embryonic development of several selected tissues, summarizing some of the most relevant findings in the central nervous system, skin, kidneys, liver, pancreas, inner ear, eye, skeleton, heart, and vascular system.


Notch Notch signaling Notch pathway Embryonic development Jagged Delta-like ligand 



Bone morphogenetic protein


Conditional knockout


Central nervous system


Dentate gyrus




Embryonic day


Fibroblast growth factor


Hairy and enhancer of split


Hair follicle


Intermediate progenitor


Intermediate progenitor cell




Lateral ventricle


Lateral wall


Mesenchymal-to-epithelial transition


Neuroepithelial cells


Notch intracellular domain


Neural stem cells


Olfactory bulb


Postnatal day


Retinoic acid


Radial glia cell


Rostral migratory stream


Subgranular zone


Sonic hedgehog


Subventricular zone


Ventricular zone




  1. Afelik S, Jensen J (2013) Notch signaling in the pancreas: patterning and cell fate specification. Wiley Interdiscip Rev Dev Biol 2:531–544. Scholar
  2. Ahnfelt-Rønne J, Jørgensen MC, Klinck R, Jensen JN, Füchtbauer E-M, Deering T, MacDonald RJ, Wright CVE, Madsen OD, Serup P (2012) Ptf1a-mediated control of Dll1 reveals an alternative to the lateral inhibition mechanism. Development 139:33–45. Scholar
  3. Andersson ER, Sandberg R, Lendahl U (2011) Notch signaling: simplicity in design, versatility in function. Development 138:3593–3612CrossRefGoogle Scholar
  4. Antoniou A, Raynaud P, Cordi S, Zong Y, Tronche F, Stanger BZ, Jacquemin P, Pierreux CE, Clotman F, Lemaigre FP (2009) Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology 136:2325–2333. Scholar
  5. Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, Hrabe de Angelis M, Lendahl U, Edlund H (1999) Notch signalling controls pancreatic cell differentiation. Nature 400:877–881. Scholar
  6. Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284(5415):770–776CrossRefGoogle Scholar
  7. Aubin-Houzelstein G (2012) Notch signaling and the developing hair follicle. Adv Exp Med Biol 727:142–160. Review. PubMed PMID: 22399345.CrossRefPubMedGoogle Scholar
  8. Bales CB, Kamath BM, Munoz PS, Nguyen A, Piccoli DA, Spinner NB, Horn D, Shults J, Leonard MB, Grimberg A et al (2010) Pathologic lower extremity fractures in children with Alagille syndrome. J Pediatr Gastroenterol Nutr 51:66–70. Scholar
  9. Basch ML, Brown RM, Jen H-I, Semerci F, Depreux F, Edlund RK, Zhang H, Norton CR, Gridley T, Cole SE et al (2016) Fine-tuning of Notch signaling sets the boundary of the organ of Corti and establishes sensory cell fates. Elife 5:841–850.
  10. Bauer RC, Laney AO, Smith R, Gerfen J, Morrissette JJD, Woyciechowski S, Garbarini J, Loomes KM, Krantz ID, Urban Z et al (2010) Jagged1 (JAG1) mutations in patients with tetralogy of fallot or pulmonic stenosis. Hum Mutat 31:594–601. Scholar
  11. Benedito R, Hellström M (2013) Notch as a hub for signaling in angiogenesis. Exp Cell Res 319:1281–1288. Scholar
  12. Benedito R, Roca C, Sörensen I, Adams S, Gossler A, Fruttiger M, Adams RH (2009) The Notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137:1124–1135. Scholar
  13. Bhatt S, Diaz R, Trainor PA (2013) Signals and switches in Mammalian neural crest cell differentiation. Cold Spring Harb Perspect Biol 5(2):a008326. Scholar
  14. Blanpain C, Lowry WE, Pasolli HA, Fuchs E (2006) Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev 20(21):3022–3035. PMCID: PMC1620020CrossRefPubMedPubMedCentralGoogle Scholar
  15. Boucher JM, Harrington A, Rostama B, Lindner V, Liaw L (2013) A receptor-specific function for Notch2 in mediating vascular smooth muscle cell growth arrest through cyclin-dependent kinase inhibitor 1B. Circ Res 113:975–985. Scholar
  16. Boyle SC, Kim M, Valerius MT, McMahon AP, Kopan R (2011) Notch pathway activation can replace the requirement for Wnt4 and Wnt9b in mesenchymal-to-epithelial transition of nephron stem cells. Development 138:4245–4254. Scholar
  17. Bray SJ (2016) Notch signalling in context. Nat Rev Mol Cell Biol 17:722–735. Scholar
  18. Brooker R, Hozumi K, Lewis J (2006) Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Development 133:1277–1286. Scholar
  19. Canalis E, Adams DJ, Boskey A, Parker K, Kranz L, Zanotti S (2013) Notch signaling in osteocytes differentially regulates cancellous and cortical bone remodeling. J Biol Chem 288:25614–25625. Scholar
  20. Canalis E, Schilling L, Yee S-P, Lee S-K, Zanotti S (2016) Hajdu Cheney mouse mutants exhibit osteopenia, increased osteoclastogenesis, and bone resorption. J Biol Chem 291:1538–1551. Scholar
  21. Cheng H-T, Kim M, Valerius MT, Surendran K, Schuster-Gossler K, Gossler A, McMahon AP, Kopan R (2007) Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. Development 134:801–811. Scholar
  22. Chiang C, Swan RZ, Grachtchouk M, Bolinger M, Litingtung Y, Robertson EK, Cooper MK, Gaffield W, Westphal H, Beachy PA, Dlugosz AA (1999) Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev Biol 205:1–9CrossRefGoogle Scholar
  23. Chung E, Deacon P, Marable S, Shin J, Park J-S (2016) Notch signaling promotes nephrogenesis by downregulating Six2. Development 143:3907–3913. Scholar
  24. Conlon RA, Reaume AG, Rossant J (1995) Notch1 is required for the coordinate segmentation of somites. Development 121:1533–1545Google Scholar
  25. Crifasi PA, Patterson MC, Michels VV (1997) Severe Hajdu-Cheney syndrome with upper airway obstruction. Am J Med Genet 70:261–266.<261::AID-AJMG9>3.0.CO;2-ZCrossRefPubMedGoogle Scholar
  26. D’Amato G, Luxán G, de la Pompa JL (2016a) Notch signalling in ventricular chamber development and cardiomyopathy. FEBS J 283:4223–4237. Scholar
  27. D’Amato G, Luxán G, del Monte-Nieto G, Martínez-Poveda B, Torroja C, Walter W, Bochter MS, Benedito R, Cole S, Martinez F et al (2016b) Sequential Notch activation regulates ventricular chamber development. Nat Cell Biol 18:7–20. Scholar
  28. de la Pompa JL, Wakeham A, Correia KM, Samper E, Brown S, Aguilera RJ, Nakano T, Honjo T, Mak TW, Rossant J, Conlon RA (1997) Conservation of the Notch signalling pathway in mammalian neurogenesis. Development 124(6):1139–1148Google Scholar
  29. Del Monte G, Casanova JC, Guadix JA, MacGrogan D, Burch JBE, Pérez-Pomares JM, de la Pompa JL (2011) Differential notch signaling in the epicardium is required for cardiac inflow development and coronary vessel morphogenesis. Circ Res 108:824–836. Scholar
  30. Devriendt K, Dooms L, Proesmans W, de Zegher F, Eggermont E, Desmet V, Devriendt K (1996) Paucity of intrahepatic bile ducts, solitary kidney and atrophic pancreas with diabetes mellitus: atypical Alagille syndrome? Eur J Pediatr 155:87–90. Scholar
  31. Dexter JS (1914) The analysis of a case of continuous variation in Drosophila by a study of its linkage relations. Am Nat 48:712–758. Scholar
  32. Dorà NJ, Collinson JM, Hill RE, West JD (2014) Hemizygous Le-Cre transgenic mice have severe eye abnormalities on some genetic backgrounds in the absence of LoxP Sites. PLoS One 9:e109193. Scholar
  33. Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA (1999) Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 29:822–829. Scholar
  34. Engler A, Zhang R, Taylor V (2018) Notch and Neurogenesis. Adv Exp Med Biol 1066:223–234. Review. PubMed PMID:30030829CrossRefPubMedGoogle Scholar
  35. Falix FA, Weeda VB, Labruyere WT, Poncy A, de Waart DR, Hakvoort TBM, Lemaigre F, Gaemers IC, Aronson DC, Lamers WH (2014) Hepatic Notch2 deficiency leads to bile duct agenesis perinatally and secondary bile duct formation after weaning. Dev Biol 396:201–213. Scholar
  36. Franco SJ, Muller U (2013) Shaping our minds: stem and progenitor cell diversity in the mammalian neocortex. Neuron 77(1):19–34. Scholar
  37. Fuchs E (2007) Scratching the surface of skin development. Nature 445(7130):834–842. PMCID: PMC2405926CrossRefPubMedPubMedCentralGoogle Scholar
  38. Fuentealba LC, Rompani SB, Parraguez JI, Obernier K, Romero R, Cepko CL, Alvarez-Buylla A (2015) Embryonic origin of postnatal neural stem cells. Cell 161(7):1644–1655. Scholar
  39. Fujimura S, Jiang Q, Kobayashi C, Nishinakamura R (2010) Notch2 activation in the embryonic kidney depletes nephron progenitors. J Am Soc Nephrol 21:803–810. Scholar
  40. Furutachi S, Miya H, Watanabe T, Kawai H, Yamasaki N, Harada Y, Imayoshi I, Nelson M, Nakayama KI, Hirabayashi Y, Gotoh Y (2015) Slowly dividing neural progenitors are an embryonic origin of adult neural stem cells. Nat Neurosci 18(5):657–665. Scholar
  41. Gaiano N, Nye JS, Fishell G (2000) Radial glial identity is promoted by Notch1 signaling in the murine forebrain. Neuron 26(2):395–404CrossRefGoogle Scholar
  42. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D (2005) Mutations in NOTCH1 cause aortic valve disease. Nature 437:270–274. Scholar
  43. Gazave E, Lapébie P, Richards GS, Brunet F, Ereskovsky AV, Degnan BM, Borchiellini C, Vervoort M, Renard E (2009) Origin and evolution of the Notch signalling pathway: an overview from eukaryotic genomes. BMC Evol Biol 9:249. Scholar
  44. Geisler F, Nagl F, Mazur PK, Lee M, Zimber-Strobl U, Strobl LJ, Radtke F, Schmid RM, Siveke JT (2008) Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology 48:607–616. Scholar
  45. Golson ML, Le Lay J, Gao N, Brämswig N, Loomes KM, Oakey R, May CL, White P, Kaestner KH (2009a) Jagged1 is a competitive inhibitor of Notch signaling in the embryonic pancreas. Mech Dev 126:687–699. Scholar
  46. Golson ML, Loomes KM, Oakey R, Kaestner KH (2009b) Ductal malformation and pancreatitis in mice caused by conditional Jag1 deletion. Gastroenterology 136:1761–1771.e1. Scholar
  47. Gordillo M, Evans T, Gouon-Evans V (2015) Orchestrating liver development. Development 142:2094–2108. Scholar
  48. Gotz M, Huttner WB (2005) The cell biology of neurogenesis. Nat Rev Mol Cell Biol 6(10):777–788. Scholar
  49. Greig LC, Woodworth MB, Galazo MJ, Padmanabhan H, Macklis JD (2013) Molecular logic of neocortical projection neuron specification, development and diversity. Nat Rev Neurosci 14(11):755–769. Scholar
  50. Gridley T (2003) Notch signaling and inherited disease syndromes. Hum Mol Genet 12:R9–R13. Scholar
  51. Grieskamp T, Rudat C, Ludtke TH-W, Norden J, Kispert A (2011) Notch signaling regulates smooth muscle differentiation of epicardium-derived cells. Circ Res 108:813–823. Scholar
  52. Gritli-Linde A, Hallberg K, Harfe BD, Reyahi A, Kannius-Janson M, Nilsson J, Cobourne MT, Sharpe PT, McMahon AP, Linde A (2007) Abnormal hair development and apparent follicular transformation to mammary gland in the absence of hedgehog signaling. Dev Cell 12:99–112CrossRefGoogle Scholar
  53. Guo C, Eckler MJ, McKenna WL, McKinsey GL, Rubenstein JL, Chen B (2013) Fezf2 expression identifies a multipotent progenitor for neocortical projection neurons, astrocytes, and oligodendrocytes. Neuron 80(5):1167–1174. Scholar
  54. Hamada Y, Kadokawa Y, Okabe M, Ikawa M, Coleman JR, Tsujimoto Y (1999) Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. Development 126:3415–3424PubMedGoogle Scholar
  55. Hansson EM, Lanner F, Das D, Mutvei A, Marklund U, Ericson J, Farnebo F, Stumm G, Stenmark H, Andersson ER et al (2010) Control of Notch-ligand endocytosis by ligand-receptor interaction. J Cell Sci 123:2931–2942. Scholar
  56. Hatakeyama J, Tomita K, Inoue T, Kageyama R (2001) Roles of homeobox and bHLH genes in specification of a retinal cell type. Development 128(8):1313–1322PubMedGoogle Scholar
  57. Hatakeyama J, Bessho Y, Katoh K, Ookawara S, Fujioka M, Guillemot F, Kageyama R (2004) Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 131(22):5539–5550. Scholar
  58. High FA, Lu MM, Pear WS, Loomes KM, Kaestner KH, Epstein JA (2008) Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc Natl Acad Sci U S A 105:1955–1959. Scholar
  59. Hill CR, Yuasa M, Schoenecker J, Goudy SL (2014) Jagged1 is essential for osteoblast development during maxillary ossification. Bone 62:10–21. Scholar
  60. Hilton MJ, Tu X, Wu X, Bai S, Zhao H, Kobayashi T, Kronenberg HM, Teitelbaum SL, Ross FP, Kopan R et al (2008) Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med 14:306–314. Scholar
  61. Hirata H, Yoshiura S, Ohtsuka T, Bessho Y, Harada T, Yoshikawa K, Kageyama R (2002) Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop. Science 298(5594):840–843. Scholar
  62. Hofmann JJ, Zovein AC, Koh H, Radtke F, Weinmaster G, Iruela-Arispe ML (2010) Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development 137:4061–4072. Scholar
  63. Hofmann JJ, Briot A, Enciso J, Zovein AC, Ren S, Zhang ZW, Radtke F, Simons M, Wang Y, Iruela-Arispe ML (2012) Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome. Development 139:4449–4460. Scholar
  64. Honjo T (1996) The shortest path from the surface to the nucleus: RBP-J kappa/Su(H) transcription factor. Genes Cells 1(1):1–9CrossRefGoogle Scholar
  65. Humphreys R, Zheng W, Prince LS, Qu X, Brown C, Loomes K, Huppert SS, Baldwin S, Goudy S (2012) Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients. Hum Mol Genet 21:1374–1383. Scholar
  66. Isidor B, Lindenbaum P, Pichon O, Bézieau S, Dina C, Jacquemont S, Martin-Coignard D, Thauvin-Robinet C, Le Merrer M, Mandel J-L et al (2011) Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet 43:306–308. Scholar
  67. Jensen J, Pedersen EE, Galante P, Hald J, Heller RS, Ishibashi M, Kageyama R, Guillemot F, Serup P, Madsen OD (2000) Control of endodermal endocrine development by Hes-1. Nat Genet 24:36–44. Scholar
  68. Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM (2000) Fate of the mammalian cardiac neural crest. Development 127:1607–1616Google Scholar
  69. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cécillion M, Maréchal E et al (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–710. Scholar
  70. Kageyama R, Ohtsuka T, Kobayashi T (2007) The Hes gene family: repressors and oscillators that orchestrate embryogenesis. Development 134(7):1243–1251. Scholar
  71. Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccoli DA, Krantz ID (2004) Vascular anomalies in Alagille Syndrome: a significant cause of morbidity and mortality. Circulation 109:1354–1358. Scholar
  72. Kamath BM, Piccoli DA, Magee JC, Sokol RJ (2012) Pancreatic insufficiency is not a prevalent problem in alagille syndrome. J Pediatr Gastroenterol Nutr 55:612–614. Scholar
  73. Kamath BM, Spinner NB, Rosenblum ND (2013) Renal involvement and the role of Notch signalling in Alagille syndrome. Nat Rev Nephrol 9:409–418. Scholar
  74. Kazanis I, Lathia J, Moss L, ffrench-Constant C (2008) The neural stem cell microenvironment. In: StemBook. Harvard Stem Cell Institute, Cambridge. Scholar
  75. Kidd S, Kelley MR, Young MW (1986) Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors. Mol Cell Biol 6(9):3094–3108CrossRefGoogle Scholar
  76. Kiernan AE, Ahituv N, Fuchs H, Balling R, Avraham KB, Steel KP, Hrabé de Angelis M (2001) The Notch ligand Jagged1 is required for inner ear sensory development. Proc Natl Acad Sci U S A 98:3873–3878. Scholar
  77. Kiernan AE, Xu J, Gridley T (2006) The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear. PLoS Genet 2:e4. Scholar
  78. Kiernan AE, Li R, Hawes NL, Churchill GA, Gridley T (2007) Genetic background modifies inner ear and eye phenotypes of Jag1 heterozygous mice. Genetics 177:307–311. Scholar
  79. Kodama Y, Hijikata M, Kageyama R, Shimotohno K, Chiba T (2004) The role of notch signaling in the development of intrahepatic bile ducts. Gastroenterology 127:1775–1786. Scholar
  80. Kopan R, Ilagan MXG (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137:216–233. Scholar
  81. Kopan R, Chen S, Liu Z (2014) Alagille, Notch, and robustness: why duplicating systems does not ensure redundancy. Pediatr Nephrol 29:651–657. Scholar
  82. Kung AWC, Xiao S-M, Cherny S, Li GHY, Gao Y, Tso G, Lau KS, Luk KDK, Liu J-M, Cui B et al (2010) Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies. Am J Hum Genet 86:229–239. Scholar
  83. Le TT, Conley KW, Brown NL (2009) Jagged 1 is necessary for normal mouse lens formation. Dev Biol 328:118–126. Scholar
  84. Le TT, Conley KW, Mead TJ, Rowan S, Yutzey KE, Brown NL (2012) Requirements for Jag1-Rbpj mediated Notch signaling during early mouse lens development. Dev Dyn 241:493–504. Scholar
  85. Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J et al (1997) Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16:243–251. Scholar
  86. Li X-Y, Zhai W-J, Teng C-B (2016) Notch signaling in pancreatic development. Int J Mol Sci 17:48. Scholar
  87. Lindström NO, Lawrence MLM, Burn SSF, Johansson JA, Bakker EERM, Ridgway RA, Chang C-H, Karolak MJM, Oxburgh L, Headon DJ et al (2015) Integrated β-catenin, BMP, PTEN, and Notch signalling patterns the nephron. Elife 3:e04000. Scholar
  88. Liu XS, Chopp M, Zhang RL, Tao T, Wang XL, Kassis H, Hozeska-Solgot A, Zhang L, Chen C, Zhang ZG (2011) MicroRNA profiling in subventricular zone after stroke: MiR-124a regulates proliferation of neural progenitor cells through Notch signaling pathway. PLoS One 6(8):e23461. Scholar
  89. Liu Z, Chen S, Boyle S, Zhu Y, Zhang A, Piwnica-Worms DR, Ilagan MXG, Kopan R (2013) The extracellular domain of notch2 increases its cell-surface abundance and ligand responsiveness during kidney development. Dev Cell 25:585–598. Scholar
  90. Loomes KM, Russo P, Ryan M, Nelson A, Underkoffler L, Glover C, Fu H, Gridley T, Kaestner KH, Oakey RJ (2007) Bile duct proliferation in liver-specific Jag1 conditional knockout mice: effects of gene dosage. Hepatology 45:323–330. Scholar
  91. Lowell S, Jones P, Le Roux I, Dunne J, Watt FM (2000) Stimulation of human epidermal differentiation by delta-notch signalling at the boundaries of stem-cell clusters. Curr Biol 10:491–500CrossRefGoogle Scholar
  92. Lupo G, Harris WA, Lewis KE (2006) Mechanisms of ventral patterning in the vertebrate nervous system. Nat Rev Neurosci 7(2):103–114. Scholar
  93. Lutolf S, Radtke F, Aguet M, Suter U, Taylor V (2002) Notch1 is required for neuronal and glial differentiation in the cerebellum. Development 129(2):373–385PubMedGoogle Scholar
  94. Luxán G, Casanova JC, Martínez-Poveda B, Prados B, D’Amato G, MacGrogan D, Gonzalez-Rajal A, Dobarro D, Torroja C, Martinez F et al (2013) Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy. Nat Med 19:193–201. Scholar
  95. Luxán G, D’Amato G, MacGrogan D, de la Pompa JL (2016) Endocardial Notch signaling in cardiac development and disease. Circ Res 118:e1–e18. Scholar
  96. MacGrogan D, D’Amato G, Travisano S, Martinez-Poveda B, Luxán G, Del Monte-Nieto G, Papoutsi T, Sbroggio M, Bou V, Gomez-Del Arco P et al (2016) Sequential ligand-dependent Notch signaling activation regulates valve primordium formation and morphogenesis. Circ Res 118:1480–1497. Scholar
  97. Manderfield LJ, High FA, Engleka KA, Liu F, Li L, Rentschler S, Epstein JA (2012) Notch activation of Jagged1 contributes to the assembly of the arterial wall. Circulation 125:314–323. Scholar
  98. Marin O (2013) Cellular and molecular mechanisms controlling the migration of neocortical interneurons. Eur J Neurosci 38(1):2019–2029. Scholar
  99. Mason HA, Rakowiecki SM, Gridley T, Fishell G (2006) Loss of notch activity in the developing central nervous system leads to increased cell death. Dev Neurosci 28(1–2):49–57. Scholar
  100. Masamizu Y, Ohtsuka T, Takashima Y, Nagahara H, Takenaka Y, Yoshikawa K, Okamura H, Kageyama R (2006) Real-time imaging of the somite segmentation clock: revelation of unstable oscillators in the individual presomitic mesoderm cells. Proc Natl Acad Sci U S A 103(5):1313–1318. Scholar
  101. Mašek J, Andersson ER (2017) The developmental biology of genetic Notch disorders. Development 2017(144):1743–1763. Scholar
  102. Massi D, Panelos J (2012) Notch signaling and the developing skin epidermis. Adv Exp Med Biol 727:131–141. Review. PubMed PMID: 22399344.CrossRefPubMedGoogle Scholar
  103. McCright B, Gao X, Shen L, Lozier J, Lan Y, Maguire M, Herzlinger D, Weinmaster G, Jiang R, Gridley T (2001) Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation. Development 128:491–502PubMedGoogle Scholar
  104. McCright B, Lozier J, Gridley T (2002) A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development 129:1075–1082PubMedGoogle Scholar
  105. McCright B, Lozier J, Gridley T (2006) Generation of new Notch2 mutant alleles. Genesis 44:29–33. Scholar
  106. Meester JAN, Verstraeten A, Alaerts M, Schepers D, Van Laer L, Loeys BL (2019) Overlapping but distinct roles for NOTCH receptors in human cardiovascular disease. Clin Genet 95(1):85–94. Epub 018 Jun 10. Review. PubMed PMID: 29767458.CrossRefPubMedGoogle Scholar
  107. Morgan TH (1917) The theory of the gene. Am Nat 19:309–310. Scholar
  108. Morgan T (1928) The theory of the gene (revised ed. 1928). Yale University Press, New Haven, pp 77–81Google Scholar
  109. Moriyama M, Durham AD, Moriyama H, Hasegawa K, Nishikawa S, Radtke F, Osawa M (2008) Multiple roles of Notch signaling in the regulation of epidermal development. Dev Cell 14:594–604CrossRefGoogle Scholar
  110. Murata J, Ohtsuka T, Tokunaga A, Nishiike S, Inohara H, Okano H, Kageyama R (2009) Notch-Hes1 pathway contributes to the cochlear prosensory formation potentially through the transcriptional down-regulation of p27Kip1. J Neurosci Res 87:3521–3534. Scholar
  111. Murtaugh LC, Stanger BZ, Kwan KM, Melton DA (2003) Notch signaling controls multiple steps of pancreatic differentiation. Proc Natl Acad Sci U S A 100:14920–14925. Scholar
  112. Nakhai H, Siveke JT, Mendoza-Torres L, Mazur PK, Algül H, Radtke F, Strobl L, Zimber-Strobl U, Schmid RM (2008) Conditional ablation of Notch signaling in pancreatic development. Development 135:2757–2765. Scholar
  113. Nguyen BC, Lefort K, Mandinova A, Antonini D, Devgan V, Della Gatta G, Koster MI, Zhang Z, Wang J, Tommasi di Vignano A et al (2006) Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev 20:1028–1042CrossRefGoogle Scholar
  114. Nicola Z, Fabel K, Kempermann G (2015) Development of the adult neurogenic niche in the hippocampus of mice. Front Neuroanat 9:53. Scholar
  115. Nobta M, Tsukazaki T, Shibata Y, Xin C, Moriishi T, Sakano S, Shindo H, Yamaguchi A (2005) Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling. J Biol Chem 280:15842–15848. Scholar
  116. Noctor SC, Martinez-Cerdeno V, Ivic L, Kriegstein AR (2004) Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci 7(2):136–144. Scholar
  117. Noctor SC, Martinez-Cerdeno V, Kriegstein AR (2007) Contribution of intermediate progenitor cells to cortical histogenesis. Arch Neurol 64(5):639–642. Scholar
  118. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS et al (1997) Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 16:235–242. Scholar
  119. Ohtsuka T, Ishibashi M, Gradwohl G, Nakanishi S, Guillemot F, Kageyama R (1999) Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation. EMBO J 18(8):2196–2207. Scholar
  120. Okuyama R, Nguyen BC, Talora C, Ogawa E, Tommasi di Vignano A, Lioumi M, Chiorino G, Tagami H, Woo M, Dotto GP (2004) High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism. Dev Cell 6:551–562CrossRefGoogle Scholar
  121. Oro AE, Higgins K (2003) Hair cycle regulation of Hedgehog signal reception. Dev Biol 255:238–248CrossRefGoogle Scholar
  122. Ozeki H, Shirai S, Majima A, Sano M, Ikeda K (1997) Clinical evaluation of posterior embryotoxon in one institution. Jpn J Ophthalmol 41:422–425. Scholar
  123. Pan W, Jin Y, Stanger B, Kiernan AE (2010) Notch signaling is required for the generation of hair cells and supporting cells in the mammalian inner ear. Proc Natl Acad Sci U S A 107:15798–15803. Scholar
  124. Pedrosa A-R, Trindade A, Fernandes A-C, Carvalho C, Gigante J, Tavares AT, Diéguez-Hurtado R, Yagita H, Adams RH, Duarte A (2015) Endothelial jagged1 antagonizes Dll4 regulation of endothelial branching and promotes vascular maturation downstream of Dll4/Notch1. Arterioscler Thromb Vasc Biol 35:1134–1146. Scholar
  125. Perez-Pomares JM, de la Pompa JL (2011) Signaling during epicardium and coronary vessel development. Circ Res 109:1429–1442. Scholar
  126. Reichrath J, Reichrath S (2019) Notch signalling and inherited diseases: challenge and promise. Adv Exp Med Biol, in press.Google Scholar
  127. Richards GS, Degnan BM (2009) The dawn of developmental signaling in the metazoa. Cold Spring Harb Symp Quant Biol 74:81–90. Scholar
  128. Riely CA, Cotlier E, Jensen PS, Klatskin G (1979) Arteriohepatic dysplasia: a benign syndrome of intrahepatic cholestasis with multiple organ involvement. Ann Intern Med 91:520–527. Scholar
  129. Rolando C, Taylor V (2014) Neural stem cell of the hippocampus: development, physiology regulation, and dysfunction in disease. Curr Top Dev Biol 107:183–206. Scholar
  130. Rovner AJ, Schall JI, Jawad AF, Piccoli DA, Stallings VA, Mulberg AE, Zemel BS (2002) Rethinking growth failure in Alagille syndrome: the role of dietary intake and steatorrhea. J Pediatr Gastroenterol Nutr 35:495–502. Scholar
  131. Saravanamuthu SS, Le TT, Gao CY, Cojocaru RI, Pandiyan P, Liu C, Zhang J, Zelenka PS, Brown NL (2012) Conditional ablation of the Notch2 receptor in the ocular lens. Dev Biol 362:219–229. Scholar
  132. Sauka-Spengler T, Bronner M (2010) Snapshot: neural crest. Cell 143(3):486–486. Scholar
  133. Scheppke L, Murphy EA, Zarpellon A, Hofmann JJ, Merkulova A, Shields DJ, Weis SM, Byzova TV, Ruggeri ZM, Iruela-arispe ML et al (2012) Notch promotes vascular maturation by inducing integrin-mediated smooth muscle cell adhesion to the endothelial basement membrane. Blood 119:2149–2158. Scholar
  134. Sedmera D (2011) Function and form in the developing cardiovascular system. Cardiovasc Res 91:252–259. Scholar
  135. Shih HP, Kopp JL, Sandhu M, Dubois CL, Seymour PA, Grapin-Botton A, Sander M (2012) A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation. Development 139:2488–2499. Scholar
  136. Shimojo H, Ohtsuka T, Kageyama R (2008) Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron 58(1):52–64. Scholar
  137. Shimojo H, Ohtsuka T, Kageyama R (2011) Dynamic expression of notch signaling genes in neural stem/progenitor cells. Front Neurosci 5:78. Scholar
  138. Stump G, Durrer A, Klein AL, Lutolf S, Suter U, Taylor V (2002) Notch1 and its ligands Delta-like and Jagged are expressed and active in distinct cell populations in the postnatal mouse brain. Mech Dev 114(1–2):153–159CrossRefGoogle Scholar
  139. Tam PP, Loebel DA (2007) Gene function in mouse embryogenesis: get set for gastrulation. Nat Rev Genet 8(5):368–381. Scholar
  140. Telley L, Govindan S, Prados J, Stevant I, Nef S, Dermitzakis E, Dayer A, Jabaudon D (2016) Sequential transcriptional waves direct the differentiation of newborn neurons in the mouse neocortex. Science 351(6280):1443–1446. Scholar
  141. Thakurdas SM, Lopez MF, Kakuda S, Fernandez-Valdivia R, Zarrin-Khameh N, Haltiwanger RS, Jafar-Nejad H (2016) Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi). Hepatology 63:550–565. Scholar
  142. Theodoris CV, Li M, White MP, Liu L, He D, Pollard KS, Bruneau BG, Srivastava D (2015) Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency. Cell 160:1072–1086. Scholar
  143. Tsai H, Hardisty RE, Rhodes C, Kiernan AE, Roby P, Tymowska-Lalanne Z, Mburu P, Rastan S, Hunter AJ, Brown SDM et al (2001) The mouse slalom mutant demonstrates a role for Jagged1 in neuroepithelial patterning in the organ of Corti. Hum Mol Genet 10:507–512. Scholar
  144. Varadkar P, Kraman M, Despres D, Ma G, Lozier J, McCright B (2008) Notch2 is required for the proliferation of cardiac neural crest-derived smooth muscle cells. Dev Dyn 237:1144–1152. Scholar
  145. Vrijens K, Thys S, De Jeu MT, Postnov AA, Pfister M, Cox L, Zwijsen A, Van Hoof V, Mueller M, De Clerck NM et al (2006) Ozzy, a Jag1 vestibular mouse mutant, displays characteristics of Alagille syndrome. Neurobiol Dis 24:28–40. Scholar
  146. Walter TJ, Vanderpool C, Cast AE, Huppert SS (2014) Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj. Am J Pathol 184:1479–1488. Scholar
  147. Wang X, Pasolli HA, Williams T, Fuchs E (2008) AP-2 factors act in concert with Notch to orchestrate terminal differentiation in skin epidermis. J Cell Biol 183:37–48CrossRefGoogle Scholar
  148. Wang Q, Zhao N, Kennard S, Lilly B (2012) Notch2 and notch3 function together to regulate vascular smooth muscle development. PLoS One 7:e37365. Scholar
  149. Weller M, Krautler N, Mantei N, Suter U, Taylor V, (2006) Jagged1 ablation results in cerebellar granule, cell migration defects and depletion of Bergmann glia. Dev Neurosci 28(1–2):70–80.
  150. Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S (1985) Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 43(3 Pt 2):567–581CrossRefGoogle Scholar
  151. Xue Y, Gao X, Lindsell CE, Norton CR, Chang B, Hicks C, Gendron-Maguire M, Rand EB, Weinmaster G, Gridley T (1999) Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet 8:723–730. Scholar
  152. Yang J, Bücker S, Jungblut B, Böttger T, Cinnamon Y, Tchorz J, Müller M, Bettler B, Harvey R, Sun Q-Y et al (2012) Inhibition of Notch2 by numb/Numblike controls myocardial compaction in the heart. Cardiovasc Res 96:276–285. Scholar
  153. Youngstrom DW, Dishowitz MI, Bales CB, Carr E, Mutyaba PL, Kozloff KM, Shitaye H, Hankenson KD, Loomes KM (2016) Jagged1 expression by osteoblast-lineage cells regulates trabecular bone mass and periosteal expansion in mice. Bone 91:64–74. Scholar
  154. Zanotti S, Canalis E (2013) Notch signaling in skeletal health and disease. Eur J Endocrinol 168(6):R95–R103. Print 2013 Jun. Review. PubMed PMID: 23554451; PubMed Central PMCID: PMC4501254.CrossRefPubMedPubMedCentralGoogle Scholar
  155. Zanotti S, Canalis E (2016) Notch signaling and the skeleton. Endocr Rev 37:223–253. Scholar
  156. Zhou Y, Tanzie C, Yan Z, Chen S, Duncan M, Gaudenz K, Li H, Seidel C, Lewis B, Moran A et al (2013) Notch2 regulates BMP signaling and epithelial morphogenesis in the ciliary body of the mouse eye. Proc Natl Acad Sci U S A 110:8966–8971. Scholar
  157. Zong Y, Panikkar A, Xu J, Antoniou A, Raynaud P, Lemaigre F, Stanger BZ (2009) Notch signaling controls liver development by regulating biliary differentiation. Development 136:1727–1739. Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of DermatologyThe Saarland University HospitalHomburgGermany

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