Notch and Stem Cells

  • Anna BigasEmail author
  • Cristina Porcheri
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1066)


The Notch pathway is crucial in the regulation of stem cells biology. Notch-mediated signalling controls several aspects of tissue homeostasis in both embryonic and adult tissues, balancing stem cells maintenance and differentiation. Although the major elements of the pathway are well conserved throughout evolution, its fine regulation varies among different systems. In this review, we are focusing at the differences and analogies of Notch activity in different animal models, comparing stem cells of various tissues in both adulthood and development. We summarize the major mode of action of the Notch-pathway in dependency to the type of ligand, cross-talk control and transcriptional regulation adopted by stem cells to preserve their undifferentiation status or complete their maturation.


Notch Self-renewing Differentiation Stem cells 







Recombination signal binding protein for immunoglobulin kappa J region




Embryonic stem cells


Leukemia inhibitory factor


Bone morphogenetic protein


Neural stem cells


Sensory organ precursor


Glial fibrillary acidic protein


Epidermal growth factor


Hematopoietic stem cells


Erythroid-myeloid progenitors


Hairy and enhancer of split 1


Hairy/enhancer-of-split related with YRPW motif 2


Transactivation domain




Bone marrow


Double negative (thymocytes)


T-cell receptor


Lymphocyte T-helper1


Lymphocyte T-helper2


T-cell acute lymphoblastic leukemia


Chronic lymphocytic leukemia of the B-cell lineage


Leucine rich repeat containing G protein-coupled receptor 5


Interfollicular epidermis


Hair follicles


Sebaceous glands


Rho-associated protein kinase 2


Reversion-inducing Cysteine-rich Protein with Kazal Motifs


A disintegrin and metalloproteinase


NOTCH-regulated ankyrin repeat-containing protein


Myogenic differentiation antigen


TNF-receptor-associated factor 6


Protein O-glucosyltransferase 1


Phosphatase and tensin homologue


Paired homeobox transcription factors


Brahma-related gene-1


Adenomatous polyposis coli


Nemo-like kinase


Glycerophosphodiester phosphodiesterase 2



We would like to thank L. Espinosa for comments and discussion on the manuscript and H.B.F. Pohl for the help with the graphics. This work was supported by Spanish Ministry of Economy and Innovation (MINECO) (SAF2013-40922-R and SAF2016 -75613-R). CP is a recipient of Juan de la Cierva fellowship (FJCI2014-19870).

The authors declare no competing financial interests.


  1. Ables JL, Decarolis NA, Johnson MA, Rivera PD, Gao Z, Cooper DC, Radtke F, Hsieh J, Eisch AJ (2010) Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells. J Neurosci 30(31):10484–10492. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Aguirre A, Rubio ME, Gallo V (2010) Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature 467(7313):323–327. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Ahmed I, Chandrakesan P, Tawfik O, Xia L, Anant S, Umar S (2012) Critical roles of Notch and Wnt/beta-catenin pathways in the regulation of hyperplasia and/or colitis in response to bacterial infection. Infect Immun 80(9):3107–3121. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R, McKay RD (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442(7104):823–826. CrossRefPubMedGoogle Scholar
  5. Artavanis-Tsakonas S, Delidakis C, Fehon RG (1991) The Notch locus and the cell biology of neuroblast segregation. Annu Rev Cell Biol 7:427–452. CrossRefPubMedGoogle Scholar
  6. Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284(5415):770–776CrossRefPubMedPubMedCentralGoogle Scholar
  7. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449(7165):1003–1007. CrossRefPubMedGoogle Scholar
  8. Basak O, Giachino C, Fiorini E, Macdonald HR, Taylor V (2012) Neurogenic subventricular zone stem/progenitor cells are Notch1-dependent in their active but not quiescent state. J Neurosci 32(16):5654–5666. CrossRefPubMedGoogle Scholar
  9. Benner EJ, Luciano D, Jo R, Abdi K, Paez-Gonzalez P, Sheng H, Warner DS, Liu C, Eroglu C, Kuo CT (2013) Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature 497(7449):369–373. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Berdnik D, Torok T, Gonzalez-Gaitan M, Knoblich JA (2002) The endocytic protein alpha-Adaptin is required for numb-mediated asymmetric cell division in Drosophila. Dev Cell 3(2):221–231CrossRefPubMedGoogle Scholar
  11. Bertet C, Li X, Erclik T, Cavey M, Wells B, Desplan C (2014) Temporal patterning of neuroblasts controls Notch-mediated cell survival through regulation of Hid or Reaper. Cell 158(5):1173–1186. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Bjornson CR, Cheung TH, Liu L, Tripathi PV, Steeper KM, Rando TA (2012) Notch signaling is necessary to maintain quiescence in adult muscle stem cells. Stem Cells 30(2):232–242. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Blanpain C, Fuchs E (2006) Epidermal stem cells of the skin. Annu Rev Cell Dev Biol 22:339–373. CrossRefPubMedPubMedCentralGoogle 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. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Borrell V, Cardenas A, Ciceri G, Galceran J, Flames N, Pla R, Nobrega-Pereira S, Garcia-Frigola C, Peregrin S, Zhao Z, Ma L, Tessier-Lavigne M, Marin O (2012) Slit/Robo signaling modulates the proliferation of central nervous system progenitors. Neuron 76(2):338–352. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Brack AS, Rando TA (2012) Tissue-specific stem cells: lessons from the skeletal muscle satellite cell. Cell Stem Cell 10(5):504–514. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Bray S (1998) A Notch affair. Cell 93(4):499–503CrossRefPubMedGoogle Scholar
  18. Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7(9):678–689. CrossRefPubMedGoogle Scholar
  19. Bray SJ (2016) Notch signalling in context. Nat Rev Mol Cell Biol 17(11):722–735. CrossRefPubMedGoogle Scholar
  20. Brohl D, Vasyutina E, Czajkowski MT, Griger J, Rassek C, Rahn HP, Purfurst B, Wende H, Birchmeier C (2012) Colonization of the satellite cell niche by skeletal muscle progenitor cells depends on Notch signals. Dev Cell 23(3):469–481. CrossRefPubMedGoogle Scholar
  21. Brooker R, Hozumi K, Lewis J (2006) Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Development 133(7):1277–1286. CrossRefPubMedGoogle Scholar
  22. Bu P, Chen KY, Chen JH, Wang L, Walters J, Shin YJ, Goerger JP, Sun J, Witherspoon M, Rakhilin N, Li J, Yang H, Milsom J, Lee S, Zipfel W, Jin MM, Gumus ZH, Lipkin SM, Shen X (2013) A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells. Cell Stem Cell 12(5):602–615. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Bu P, Wang L, Chen KY, Srinivasan T, Murthy PK, Tung KL, Varanko AK, Chen HJ, Ai Y, King S, Lipkin SM, Shen X (2016) A miR-34a-Numb feedforward loop triggered by inflammation regulates asymmetric stem cell division in intestine and colon cancer. Cell Stem Cell 18(2):189–202. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Buckingham M, Relaix F (2007) The role of Pax genes in the development of tissues and organs: Pax3 and Pax7 regulate muscle progenitor cell functions. Annu Rev Cell Dev Biol 23:645–673. CrossRefPubMedGoogle Scholar
  25. Butko E, Pouget C, Traver D (2016) Complex regulation of HSC emergence by the Notch signaling pathway. Dev Biol 409(1):129–138. CrossRefPubMedGoogle Scholar
  26. Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT, Seandel M, Shido K, White IA, Kobayashi M, Witte L, May C, Shawber C, Kimura Y, Kitajewski J, Rosenwaks Z, Bernstein ID, Rafii S (2010) Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell 6(3):251–264. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425(6960):841–846. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Cappellari O, Benedetti S, Innocenzi A, Tedesco FS, Moreno-Fortuny A, Ugarte G, Lampugnani MG, Messina G, Cossu G (2013) Dll4 and PDGF-BB convert committed skeletal myoblasts to pericytes without erasing their myogenic memory. Dev Cell 24(6):586–599. CrossRefPubMedGoogle Scholar
  29. Carulli AJ, Keeley TM, Demitrack ES, Chung J, Maillard I, Samuelson LC (2015) Notch receptor regulation of intestinal stem cell homeostasis and crypt regeneration. Dev Biol 402(1):98–108. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Caviness VS Jr, Nowakowski RS, Bhide PG (2009) Neocortical neurogenesis: morphogenetic gradients and beyond. Trends Neurosci 32(8):443–450. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Cayouette M, Raff M (2002) Asymmetric segregation of Numb: a mechanism for neural specification from Drosophila to mammals. Nat Neurosci 5(12):1265–1269. CrossRefPubMedGoogle Scholar
  32. Chambers CB, Peng Y, Nguyen H, Gaiano N, Fishell G, Nye JS (2001) Spatiotemporal selectivity of response to Notch1 signals in mammalian forebrain precursors. Development 128(5):689–702PubMedGoogle Scholar
  33. Chenn A, McConnell SK (1995) Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Cell 82(4):631–641CrossRefPubMedGoogle Scholar
  34. Chi Z, Zhang J, Tokunaga A, Harraz MM, Byrne ST, Dolinko A, Xu J, Blackshaw S, Gaiano N, Dawson TM, Dawson VL (2012) Botch promotes neurogenesis by antagonizing Notch. Dev Cell 22(4):707–720. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Ciau-Uitz A, Walmsley M, Patient R (2000) Distinct origins of adult and embryonic blood in Xenopus. Cell 102(6):787–796CrossRefPubMedGoogle Scholar
  36. Clarke RL, Yzaguirre AD, Yashiro-Ohtani Y, Bondue A, Blanpain C, Pear WS, Speck NA, Keller G (2013) The expression of Sox17 identifies and regulates haemogenic endothelium. Nat Cell Biol 15(5):502–510. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Conboy IM, Conboy MJ, Smythe GM, Rando TA (2003) Notch-mediated restoration of regenerative potential to aged muscle. Science 302(5650):1575–1577. CrossRefPubMedGoogle Scholar
  38. Coumailleau F, Furthauer M, Knoblich JA, Gonzalez-Gaitan M (2009) Directional Delta and Notch trafficking in Sara endosomes during asymmetric cell division. Nature 458(7241):1051–1055. CrossRefPubMedGoogle Scholar
  39. Czajkowski MT, Rassek C, Lenhard DC, Brohl D, Birchmeier C (2014) Divergent and conserved roles of Dll1 signaling in development of craniofacial and trunk muscle. Dev Biol 395(2):307–316. CrossRefPubMedGoogle Scholar
  40. Daudet N, Lewis J (2005) Two contrasting roles for Notch activity in chick inner ear development: specification of prosensory patches and lateral inhibition of hair-cell differentiation. Development 132(3):541–551. CrossRefPubMedGoogle Scholar
  41. Davis RL, Turner DL (2001) Vertebrate hairy and Enhancer of split related proteins: transcriptional repressors regulating cellular differentiation and embryonic patterning. Oncogene 20(58):8342–8357. CrossRefPubMedGoogle Scholar
  42. de Celis JF, Bray S (1997) Feed-back mechanisms affecting Notch activation at the dorsoventral boundary in the Drosophila wing. Development 124(17):3241–3251PubMedGoogle Scholar
  43. de Jong JL, Zon LI (2005) Use of the zebrafish system to study primitive and definitive hematopoiesis. Annu Rev Genet 39:481–501. CrossRefPubMedGoogle Scholar
  44. del Alamo D, Rouault H, Schweisguth F (2011) Mechanism and significance of cis-inhibition in Notch signalling. Curr Biol 21(1):R40–R47. CrossRefPubMedGoogle Scholar
  45. Del Bene F, Wehman AM, Link BA, Baier H (2008) Regulation of neurogenesis by interkinetic nuclear migration through an apical-basal notch gradient. Cell 134(6):1055–1065. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Dieterlen-Lievre F, Martin C (1981) Diffuse intraembryonic hemopoiesis in normal and chimeric avian development. Dev Biol 88(1):180–191CrossRefPubMedGoogle Scholar
  47. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97(6):703–716CrossRefPubMedGoogle Scholar
  48. Dong Z, Yang N, Yeo SY, Chitnis A, Guo S (2012) Intralineage directional Notch signaling regulates self-renewal and differentiation of asymmetrically dividing radial glia. Neuron 74(1):65–78. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Duarte A, Hirashima M, Benedito R, Trindade A, Diniz P, Bekman E, Costa L, Henrique D, Rossant J (2004) Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev 18(20):2474–2478. CrossRefPubMedPubMedCentralGoogle Scholar
  50. Dzierzak E, Speck NA (2008) Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nat Immunol 9(2):129–136. CrossRefPubMedPubMedCentralGoogle Scholar
  51. Ehm O, Goritz C, Covic M, Schaffner I, Schwarz TJ, Karaca E, Kempkes B, Kremmer E, Pfrieger FW, Espinosa L, Bigas A, Giachino C, Taylor V, Frisen J, Lie DC (2010) RBPJkappa-dependent signaling is essential for long-term maintenance of neural stem cells in the adult hippocampus. J Neurosci 30(41):13794–13807. CrossRefPubMedGoogle Scholar
  52. van Es JH, de Geest N, van de Born M, Clevers H, Hassan BA (2010) Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors. Nat Commun 1:18. CrossRefPubMedGoogle Scholar
  53. Espin-Palazon R, Stachura DL, Campbell CA, Garcia-Moreno D, Del Cid N, Kim AD, Candel S, Meseguer J, Mulero V, Traver D (2014) Proinflammatory signaling regulates hematopoietic stem cell emergence. Cell 159(5):1070–1085. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Estrach S, Ambler CA, Lo Celso C, Hozumi K, Watt FM (2006) Jagged 1 is a beta-catenin target gene required for ectopic hair follicle formation in adult epidermis. Development 133(22):4427–4438. CrossRefPubMedGoogle Scholar
  55. Estrach S, Legg J, Watt FM (2007) Syntenin mediates Delta1-induced cohesiveness of epidermal stem cells in culture. J Cell Sci 120(Pt 16):2944–2952. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Estrach S, Cordes R, Hozumi K, Gossler A, Watt FM (2008) Role of the Notch ligand Delta1 in embryonic and adult mouse epidermis. J Invest Dermatol 128(4):825–832. CrossRefPubMedGoogle Scholar
  57. Favier B, Fliniaux I, Thelu J, Viallet JP, Demarchez M, Jahoda CA, Dhouailly D (2000) Localisation of members of the notch system and the differentiation of vibrissa hair follicles: receptors, ligands, and fringe modulators. Dev Dyn 218(3):426–437.<426::AID-DVDY1004>3.0.CO;2-4 CrossRefPubMedGoogle Scholar
  58. Ferron SR, Charalambous M, Radford E, McEwen K, Wildner H, Hind E, Morante-Redolat JM, Laborda J, Guillemot F, Bauer SR, Farinas I, Ferguson-Smith AC (2011) Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis. Nature 475(7356):381–385. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Fortini ME (2009) Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 16(5):633–647. CrossRefPubMedGoogle Scholar
  60. Fre S, Huyghe M, Mourikis P, Robine S, Louvard D, Artavanis-Tsakonas S (2005) Notch signals control the fate of immature progenitor cells in the intestine. Nature 435(7044):964–968. CrossRefPubMedGoogle Scholar
  61. Fre S, Pallavi SK, Huyghe M, Lae M, Janssen KP, Robine S, Artavanis-Tsakonas S, Louvard D (2009) Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc Natl Acad Sci U S A 106(15):6309–6314. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Fre S, Hannezo E, Sale S, Huyghe M, Lafkas D, Kissel H, Louvi A, Greve J, Louvard D, Artavanis-Tsakonas S (2011) Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice. PLoS One 6(10):e25785. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Fuchs E (2008) Skin stem cells: rising to the surface. J Cell Biol 180(2):273–284. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Furthauer M, Gonzalez-Gaitan M (2009a) Endocytic regulation of notch signalling during development. Traffic 10(7):792–802. CrossRefPubMedGoogle Scholar
  65. Furthauer M, Gonzalez-Gaitan M (2009b) Endocytosis, asymmetric cell division, stem cells and cancer: unus pro omnibus, omnes pro uno. Mol Oncol 3(4):339–353. CrossRefPubMedPubMedCentralGoogle Scholar
  66. Gage FH (2000) Mammalian neural stem cells. Science 287(5457):1433–1438CrossRefPubMedGoogle Scholar
  67. Gage FH, Coates PW, Palmer TD, Kuhn HG, Fisher LJ, Suhonen JO, Peterson DA, Suhr ST, Ray J (1995) Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci U S A 92(25):11879–11883CrossRefPubMedPubMedCentralGoogle Scholar
  68. Gaiano N, Fishell G (2002) The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci 25:471–490. CrossRefPubMedGoogle Scholar
  69. Gaiano N, Nye JS, Fishell G (2000) Radial glial identity is promoted by Notch1 signaling in the murine forebrain. Neuron 26(2):395–404CrossRefPubMedGoogle Scholar
  70. Gama-Norton L, Ferrando E, Ruiz-Herguido C, Liu Z, Guiu J, Islam AB, Lee SU, Yan M, Guidos CJ, Lopez-Bigas N, Maeda T, Espinosa L, Kopan R, Bigas A (2015) Notch signal strength controls cell fate in the haemogenic endothelium. Nat Commun 6:8510. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Gekas C, Dieterlen-Lievre F, Orkin SH, Mikkola HK (2005) The placenta is a niche for hematopoietic stem cells. Dev Cell 8(3):365–375. CrossRefPubMedGoogle Scholar
  72. Gerhardt DM, Pajcini KV, D'Altri T, Tu L, Jain R, Xu L, Chen MJ, Rentschler S, Shestova O, Wertheim GB, Tobias JW, Kluk M, Wood AW, Aster JC, Gimotty PA, Epstein JA, Speck N, Bigas A, Pear WS (2014) The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells. Genes Dev 28(6):576–593. CrossRefPubMedPubMedCentralGoogle Scholar
  73. Gifford GB, Demitrack ES, Keeley TM, Tam A, La Cunza N, Dedhia PH, Spence JR, Simeone DM, Saotome I, Louvi A, Siebel CW, Samuelson LC (2016) Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis. Gut.
  74. Givogri MI, de Planell M, Galbiati F, Superchi D, Gritti A, Vescovi A, de Vellis J, Bongarzone ER (2006) Notch signaling in astrocytes and neuroblasts of the adult subventricular zone in health and after cortical injury. Dev Neurosci 28(1–2):81–91. CrossRefPubMedGoogle Scholar
  75. Gotz M, Huttner WB (2005) The cell biology of neurogenesis. Nat Rev Mol Cell Biol 6(10):777–788. CrossRefPubMedGoogle Scholar
  76. Guilmeau S (2012) Notch signaling and intestinal cancer. Adv Exp Med Biol 727:272–288. CrossRefPubMedGoogle Scholar
  77. Guiu J, Shimizu R, D'Altri T, Fraser ST, Hatakeyama J, Bresnick EH, Kageyama R, Dzierzak E, Yamamoto M, Espinosa L, Bigas A (2013) Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling. J Exp Med 210(1):71–84. CrossRefPubMedPubMedCentralGoogle Scholar
  78. Hadland BK, Huppert SS, Kanungo J, Xue Y, Jiang R, Gridley T, Conlon RA, Cheng AM, Kopan R, Longmore GD (2004) A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development. Blood 104(10):3097–3105. CrossRefPubMedPubMedCentralGoogle Scholar
  79. Hadland BK, Varnum-Finney B, Poulos MG, Moon RT, Butler JM, Rafii S, Bernstein ID (2015) Endothelium and NOTCH specify and amplify aorta-gonad-mesonephros-derived hematopoietic stem cells. J Clin Invest 125(5):2032–2045. CrossRefPubMedPubMedCentralGoogle Scholar
  80. Hansen DV, Lui JH, Parker PR, Kriegstein AR (2010) Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464(7288):554–561. CrossRefPubMedGoogle Scholar
  81. Haydar TF, Jr. Ang E, Rakic P (2003) Mitotic spindle rotation and mode of cell division in the developing telencephalon. Proc Natl Acad Sci U S A 100(5):2890–2895. CrossRefPubMedPubMedCentralGoogle Scholar
  82. He Q, Zhang C, Wang L, Zhang P, Ma D, Lv J, Liu F (2015) Inflammatory signaling regulates hematopoietic stem and progenitor cell emergence in vertebrates. Blood 125(7):1098–1106. CrossRefPubMedGoogle Scholar
  83. Heitzler P, Simpson P (1991) The choice of cell fate in the epidermis of Drosophila. Cell 64(6):1083–1092CrossRefPubMedGoogle Scholar
  84. Hindi SM, Paul PK, Dahiya S, Mishra V, Bhatnagar S, Kuang S, Choi Y, Kumar A (2012) Reciprocal interaction between TRAF6 and notch signaling regulates adult myofiber regeneration upon injury. Mol Cell Biol 32(23):4833–4845. CrossRefPubMedPubMedCentralGoogle Scholar
  85. Hirata A, Utikal J, Yamashita S, Aoki H, Watanabe A, Yamamoto T, Okano H, Bardeesy N, Kunisada T, Ushijima T, Hara A, Jaenisch R, Hochedlinger K, Yamada Y (2013) Dose-dependent roles for canonical Wnt signalling in de novo crypt formation and cell cycle properties of the colonic epithelium. Development 140(1):66–75. CrossRefPubMedPubMedCentralGoogle Scholar
  86. Hoeck JD, Jandke A, Blake SM, Nye E, Spencer-Dene B, Brandner S, Behrens A (2010) Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun. Nat Neurosci 13(11):1365–1372. CrossRefPubMedGoogle Scholar
  87. Hori K, Sen A, Artavanis-Tsakonas S (2013) Notch signaling at a glance. J Cell Sci 126(Pt 10):2135–2140. CrossRefPubMedPubMedCentralGoogle Scholar
  88. Huber TL, Kouskoff V, Fehling HJ, Palis J, Keller G (2004) Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature 432(7017):625–630. CrossRefPubMedGoogle Scholar
  89. Huppert SS, Ilagan MX, De Strooper B, Kopan R (2005) Analysis of Notch function in presomitic mesoderm suggests a gamma-secretase-independent role for presenilins in somite differentiation. Dev Cell 8(5):677–688. CrossRefPubMedGoogle Scholar
  90. Hutterer A, Knoblich JA (2005) Numb and alpha-Adaptin regulate Sanpodo endocytosis to specify cell fate in Drosophila external sensory organs. EMBO Rep 6(9):836–842. CrossRefPubMedPubMedCentralGoogle Scholar
  91. Imayoshi I, Isomura A, Harima Y, Kawaguchi K, Kori H, Miyachi H, Fujiwara T, Ishidate F, Kageyama R (2013) Oscillatory control of factors determining multipotency and fate in mouse neural progenitors. Science 342(6163):1203–1208. CrossRefPubMedGoogle Scholar
  92. Inman KE, Downs KM (2007) The murine allantois: emerging paradigms in development of the mammalian umbilical cord and its relation to the fetus. Genesis 45(5):237–258. CrossRefPubMedGoogle Scholar
  93. Irvin DK, Nakano I, Paucar A, Kornblum HI (2004) Patterns of Jagged1, Jagged2, Delta-like 1 and Delta-like 3 expression during late embryonic and postnatal brain development suggest multiple functional roles in progenitors and differentiated cells. J Neurosci Res 75(3):330–343. CrossRefPubMedGoogle Scholar
  94. Ishibashi M, Moriyoshi K, Sasai Y, Shiota K, Nakanishi S, Kageyama R (1994) Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central nervous system. EMBO J 13(8):1799–1805PubMedPubMedCentralCrossRefGoogle Scholar
  95. Ishitani T, Hirao T, Suzuki M, Isoda M, Ishitani S, Harigaya K, Kitagawa M, Matsumoto K, Itoh M (2010) Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex. Nat Cell Biol 12(3):278–285. CrossRefPubMedGoogle Scholar
  96. Iso T, Kedes L, Hamamori Y (2003) HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 194(3):237–255. CrossRefPubMedGoogle Scholar
  97. Ivanovs A, Rybtsov S, Anderson RA, Turner ML, Medvinsky A (2014) Identification of the niche and phenotype of the first human hematopoietic stem cells. Stem Cell Reports 2(4):449–456. CrossRefPubMedPubMedCentralGoogle Scholar
  98. Jehn BM, Bielke W, Pear WS, Osborne BA (1999) Cutting edge: protective effects of notch-1 on TCR-induced apoptosis. J Immunol 162(2):635–638PubMedGoogle Scholar
  99. Jensen UB, Lowell S, Watt FM (1999) The spatial relationship between stem cells and their progeny in the basal layer of human epidermis: a new view based on whole-mount labelling and lineage analysis. Development 126(11):2409–2418PubMedGoogle Scholar
  100. Kageyama R, Niwa Y, Isomura A, Gonzalez A, Harima Y (2012) Oscillatory gene expression and somitogenesis. Wiley Interdiscip Rev Dev Biol 1(5):629–641. CrossRefPubMedGoogle Scholar
  101. Kanz D, Konantz M, Alghisi E, North TE, Lengerke C (2016) Endothelial-to-hematopoietic transition: Notch-ing vessels into blood. Ann N Y Acad Sci 1370(1):97–108. CrossRefPubMedGoogle Scholar
  102. Karanu FN, Murdoch B, Gallacher L, Wu DM, Koremoto M, Sakano S, Bhatia M (2000) The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J Exp Med 192(9):1365–1372CrossRefPubMedPubMedCentralGoogle Scholar
  103. Kazanjian A, Shroyer NF (2011) NOTCH Signaling and ATOH1 in Colorectal Cancers. Curr Colorectal Cancer Rep 7(2):121–127. CrossRefPubMedPubMedCentralGoogle Scholar
  104. Kim J, Sebring A, Esch JJ, Kraus ME, Vorwerk K, Magee J, Carroll SB (1996) Integration of positional signals and regulation of wing formation and identity by Drosophila vestigial gene. Nature 382(6587):133–138. CrossRefPubMedGoogle Scholar
  105. Kim TH, Li F, Ferreiro-Neira I, Ho LL, Luyten A, Nalapareddy K, Long H, Verzi M, Shivdasani RA (2014) Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity. Nature 506(7489):511–515. CrossRefPubMedPubMedCentralGoogle Scholar
  106. Kim JH, Han GC, Seo JY, Park I, Park W, Jeong HW, Lee SH, Bae SH, Seong J, Yum MK, Hann SH, Kwon YG, Seo D, Choi MH, Kong YY (2016) Sex hormones establish a reserve pool of adult muscle stem cells. Nat Cell Biol 18(9):930–940. CrossRefPubMedGoogle Scholar
  107. Kitamoto T, Hanaoka K (2010) Notch3 null mutation in mice causes muscle hyperplasia by repetitive muscle regeneration. Stem Cells 28(12):2205–2216. CrossRefPubMedGoogle Scholar
  108. Kivela R, Salmela I, Nguyen YH, Petrova TV, Koistinen HA, Wiener Z, Alitalo K (2016) The transcription factor Prox1 is essential for satellite cell differentiation and muscle fibre-type regulation. Nat Commun 7:13124. CrossRefPubMedPubMedCentralGoogle Scholar
  109. Knoblich JA (2001) Asymmetric cell division during animal development. Nat Rev Mol Cell Biol 2(1):11–20. CrossRefPubMedGoogle Scholar
  110. Knoblich JA (2008) Mechanisms of asymmetric stem cell division. Cell 132(4):583–597. CrossRefPubMedGoogle Scholar
  111. Knoblich JA, Jan LY, Jan YN (1995) Asymmetric segregation of Numb and Prospero during cell division. Nature 377(6550):624–627. CrossRefPubMedGoogle Scholar
  112. Kobayashi T, Mizuno H, Imayoshi I, Furusawa C, Shirahige K, Kageyama R (2009) The cyclic gene Hes1 contributes to diverse differentiation responses of embryonic stem cells. Genes Dev 23(16):1870–1875. CrossRefPubMedPubMedCentralGoogle Scholar
  113. Koch U, Lehal R, Radtke F (2013) Stem cells living with a Notch. Development 140(4):689–704. CrossRefPubMedGoogle Scholar
  114. Kong JH, Yang L, Dessaud E, Chuang K, Moore DM, Rohatgi R, Briscoe J, Novitch BG (2015) Notch activity modulates the responsiveness of neural progenitors to sonic hedgehog signaling. Dev Cell 33(4):373–387. CrossRefPubMedPubMedCentralGoogle Scholar
  115. Kopan R, Weintraub H (1993) Mouse notch: expression in hair follicles correlates with cell fate determination. J Cell Biol 121(3):631–641CrossRefPubMedGoogle Scholar
  116. Kopan R, Nye JS, Weintraub H (1994) The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD. Development 120(9):2385–2396PubMedGoogle Scholar
  117. Kosodo Y, Roper K, Haubensak W, Marzesco AM, Corbeil D, Huttner WB (2004) Asymmetric distribution of the apical plasma membrane during neurogenic divisions of mammalian neuroepithelial cells. EMBO J 23(11):2314–2324. CrossRefPubMedPubMedCentralGoogle Scholar
  118. Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP, Gallahan D, Closson V, Kitajewski J, Callahan R, Smith GH, Stark KL, Gridley T (2000) Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 14(11):1343–1352PubMedPubMedCentralGoogle Scholar
  119. Krebs LT, Shutter JR, Tanigaki K, Honjo T, Stark KL, Gridley T (2004) Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev 18(20):2469–2473. CrossRefPubMedPubMedCentralGoogle Scholar
  120. Kressmann S, Campos C, Castanon I, Furthauer M, Gonzalez-Gaitan M (2015) Directional Notch trafficking in Sara endosomes during asymmetric cell division in the spinal cord. Nat Cell Biol 17(3):333–339. CrossRefPubMedGoogle Scholar
  121. Kumano K, Chiba S, Kunisato A, Sata M, Saito T, Nakagami-Yamaguchi E, Yamaguchi T, Masuda S, Shimizu K, Takahashi T, Ogawa S, Hamada Y, Hirai H (2003) Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity 18(5):699–711CrossRefPubMedGoogle Scholar
  122. Lai EC (2004) Notch signaling: control of cell communication and cell fate. Development 131(5):965–973. CrossRefPubMedPubMedCentralGoogle Scholar
  123. Lee J, Basak JM, Demehri S, Kopan R (2007) Bi-compartmental communication contributes to the opposite proliferative behavior of Notch1-deficient hair follicle and epidermal keratinocytes. Development 134(15):2795–2806. CrossRefPubMedPubMedCentralGoogle Scholar
  124. Lee CY, Vogeli KM, Kim SH, Chong SW, Jiang YJ, Stainier DY, Jin SW (2009) Notch signaling functions as a cell-fate switch between the endothelial and hematopoietic lineages. Curr Biol 19(19):1616–1622. CrossRefPubMedPubMedCentralGoogle Scholar
  125. Lefort K, Mandinova A, Ostano P, Kolev V, Calpini V, Kolfschoten I, Devgan V, Lieb J, Raffoul W, Hohl D, Neel V, Garlick J, Chiorino G, Dotto GP (2007) Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases. Genes Dev 21(5):562–577. CrossRefPubMedPubMedCentralGoogle Scholar
  126. Lepper C, Partridge TA, Fan CM (2011) An absolute requirement for Pax7-positive satellite cells in acute injury-induced skeletal muscle regeneration. Development 138(17):3639–3646. CrossRefPubMedPubMedCentralGoogle Scholar
  127. Lewis J (1998) Notch signalling and the control of cell fate choices in vertebrates. Semin Cell Dev Biol 9(6):583–589. CrossRefPubMedGoogle Scholar
  128. Li R (2013) The art of choreographing asymmetric cell division. Dev Cell 25(5):439–450. CrossRefPubMedGoogle Scholar
  129. Li HJ, Kapoor A, Giel-Moloney M, Rindi G, Leiter AB (2012) Notch signaling differentially regulates the cell fate of early endocrine precursor cells and their maturing descendants in the mouse pancreas and intestine. Dev Biol 371(2):156–169. CrossRefPubMedPubMedCentralGoogle Scholar
  130. Liu W, Wen Y, Bi P, Lai X, Liu XS, Liu X, Kuang S (2012) Hypoxia promotes satellite cell self-renewal and enhances the efficiency of myoblast transplantation. Development 139(16):2857–2865. CrossRefPubMedPubMedCentralGoogle Scholar
  131. Lizama CO, Hawkins JS, Schmitt CE, Bos FL, Zape JP, Cautivo KM, Borges Pinto H, Rhyner AM, Yu H, Donohoe ME, Wythe JD, Zovein AC (2015) Repression of arterial genes in hemogenic endothelium is sufficient for haematopoietic fate acquisition. Nat Commun 6:7739. CrossRefPubMedPubMedCentralGoogle Scholar
  132. Lobry C, Oh P, Mansour MR, Look AT, Aifantis I (2014) Notch signaling: switching an oncogene to a tumor suppressor. Blood 123(16):2451–2459. CrossRefPubMedPubMedCentralGoogle Scholar
  133. Lopez-Arribillaga E, Rodilla V, Pellegrinet L, Guiu J, Iglesias M, Roman AC, Gutarra S, Gonzalez S, Munoz-Canoves P, Fernandez-Salguero P, Radtke F, Bigas A, Espinosa L (2015) Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch. Development 142(1):41–50. CrossRefPubMedGoogle Scholar
  134. Lopez-Garcia C, Klein AM, Simons BD, Winton DJ (2010) Intestinal stem cell replacement follows a pattern of neutral drift. Science 330(6005):822–825. CrossRefPubMedGoogle Scholar
  135. Louvi A, Artavanis-Tsakonas S (2006) Notch signalling in vertebrate neural development. Nat Rev Neurosci 7(2):93–102. CrossRefPubMedGoogle Scholar
  136. 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(9):491–500CrossRefPubMedGoogle Scholar
  137. Lowell S, Benchoua A, Heavey B, Smith AG (2006) Notch promotes neural lineage entry by pluripotent embryonic stem cells. PLoS Biol 4(5):e121. CrossRefPubMedPubMedCentralGoogle Scholar
  138. Lugert S, Basak O, Knuckles P, Haussler U, Fabel K, Gotz M, Haas CA, Kempermann G, Taylor V, Giachino C (2010) Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell 6(5):445–456. CrossRefPubMedGoogle Scholar
  139. 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
  140. Magnusson JP, Goritz C, Tatarishvili J, Dias DO, Smith EM, Lindvall O, Kokaia Z, Frisen J (2014) A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science 346(6206):237–241. CrossRefPubMedGoogle Scholar
  141. Maillard I, Koch U, Dumortier A, Shestova O, Xu L, Sai H, Pross SE, Aster JC, Bhandoola A, Radtke F, Pear WS (2008) Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell 2(4):356–366. CrossRefPubMedPubMedCentralGoogle Scholar
  142. Mammucari C, Tommasi di Vignano A, Sharov AA, Neilson J, Havrda MC, Roop DR, Botchkarev VA, Crabtree GR, Dotto GP (2005) Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control. Dev Cell 8(5):665–676. CrossRefPubMedGoogle Scholar
  143. Matsuda S, Kuwako K, Okano HJ, Tsutsumi S, Aburatani H, Saga Y, Matsuzaki Y, Akaike A, Sugimoto H, Okano H (2012) Sox21 promotes hippocampal adult neurogenesis via the transcriptional repression of the Hes5 gene. J Neurosci 32(36):12543–12557. CrossRefPubMedGoogle Scholar
  144. Mayeuf-Louchart A, Lagha M, Danckaert A, Rocancourt D, Relaix F, Vincent SD, Buckingham M (2014) Notch regulation of myogenic versus endothelial fates of cells that migrate from the somite to the limb. Proc Natl Acad Sci U S A 111(24):8844–8849. CrossRefPubMedPubMedCentralGoogle Scholar
  145. Medvinsky AL, Samoylina NL, Muller AM, Dzierzak EA (1993) An early pre-liver intraembryonic source of CFU-S in the developing mouse. Nature 364(6432):64–67. CrossRefPubMedGoogle Scholar
  146. Medvinsky A, Rybtsov S, Taoudi S (2011) Embryonic origin of the adult hematopoietic system: advances and questions. Development 138(6):1017–1031. CrossRefPubMedGoogle Scholar
  147. Mizutani K, Yoon K, Dang L, Tokunaga A, Gaiano N (2007) Differential Notch signalling distinguishes neural stem cells from intermediate progenitors. Nature 449(7160):351–355. CrossRefPubMedGoogle Scholar
  148. Moriyama M, Osawa M, Mak SS, Ohtsuka T, Yamamoto N, Han H, Delmas V, Kageyama R, Beermann F, Larue L, Nishikawa S (2006) Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells. J Cell Biol 173(3):333–339. CrossRefPubMedPubMedCentralGoogle Scholar
  149. Morrison SJ, Hemmati HD, Wandycz AM, Weissman IL (1995) The purification and characterization of fetal liver hematopoietic stem cells. Proc Natl Acad Sci U S A 92(22):10302–10306CrossRefPubMedPubMedCentralGoogle Scholar
  150. Mourikis P, Tajbakhsh S (2014) Distinct contextual roles for Notch signalling in skeletal muscle stem cells. BMC Dev Biol 14:2. CrossRefPubMedPubMedCentralGoogle Scholar
  151. Mourikis P, Gopalakrishnan S, Sambasivan R, Tajbakhsh S (2012a) Cell-autonomous Notch activity maintains the temporal specification potential of skeletal muscle stem cells. Development 139(24):4536–4548. CrossRefPubMedGoogle Scholar
  152. Mourikis P, Sambasivan R, Castel D, Rocheteau P, Bizzarro V, Tajbakhsh S (2012b) A critical requirement for notch signaling in maintenance of the quiescent skeletal muscle stem cell state. Stem Cells 30(2):243–252. CrossRefPubMedGoogle Scholar
  153. Nakagawa M, Ichikawa M, Kumano K, Goyama S, Kawazu M, Asai T, Ogawa S, Kurokawa M, Chiba S (2006) AML1/Runx1 rescues Notch1-null mutation-induced deficiency of para-aortic splanchnopleural hematopoiesis. Blood 108(10):3329–3334. CrossRefPubMedGoogle Scholar
  154. Nemir M, Croquelois A, Pedrazzini T, Radtke F (2006) Induction of cardiogenesis in embryonic stem cells via downregulation of Notch1 signaling. Circ Res 98(12):1471–1478. CrossRefPubMedGoogle Scholar
  155. Neumuller RA, Knoblich JA (2009) Dividing cellular asymmetry: asymmetric cell division and its implications for stem cells and cancer. Genes Dev 23(23):2675–2699. CrossRefPubMedPubMedCentralGoogle Scholar
  156. Nickoloff BJ, Qin JZ, Chaturvedi V, Denning MF, Bonish B, Miele L (2002) Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma. Cell Death Differ 9(8):842–855. CrossRefPubMedGoogle Scholar
  157. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, Hui CC, Clevers H, Dotto GP, Radtke F (2003) Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 33(3):416–421. CrossRefPubMedGoogle Scholar
  158. Noah TK, Shroyer NF (2013) Notch in the intestine: regulation of homeostasis and pathogenesis. Annu Rev Physiol 75:263–288. CrossRefPubMedGoogle Scholar
  159. Noggle SA, Weiler D, Condie BG (2006) Notch signaling is inactive but inducible in human embryonic stem cells. Stem Cells 24(7):1646–1653. CrossRefPubMedGoogle Scholar
  160. Nyfeler Y, Kirch RD, Mantei N, Leone DP, Radtke F, Suter U, Taylor V (2005) Jagged1 signals in the postnatal subventricular zone are required for neural stem cell self-renewal. EMBO J 24(19):3504–3515. CrossRefPubMedPubMedCentralGoogle Scholar
  161. Oh P, Lobry C, Gao J, Tikhonova A, Loizou E, Manent J, van Handel B, Ibrahim S, Greve J, Mikkola H, Artavanis-Tsakonas S, Aifantis I (2013) In vivo mapping of notch pathway activity in normal and stress hematopoiesis. Cell Stem Cell 13(2):190–204. CrossRefPubMedPubMedCentralGoogle Scholar
  162. Ohishi K, Varnum-Finney B, Bernstein ID (2002) Delta-1 enhances marrow and thymus repopulating ability of human CD34(+)CD38(-) cord blood cells. J Clin Invest 110(8):1165–1174. CrossRefPubMedPubMedCentralGoogle Scholar
  163. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  164. Oka C, Nakano T, Wakeham A, de la Pompa JL, Mori C, Sakai T, Okazaki S, Kawaichi M, Shiota K, Mak TW, Honjo T (1995) Disruption of the mouse RBP-J kappa gene results in early embryonic death. Development 121(10):3291–3301PubMedGoogle Scholar
  165. Okumura T, Takeda K, Kuchiki M, Akaishi M, Taniguchi K, Adachi-Yamada T (2016) GATAe regulates intestinal stem cell maintenance and differentiation in Drosophila adult midgut. Dev Biol 410(1):24–35. CrossRefPubMedGoogle Scholar
  166. Osborne BA, Minter LM (2007) Notch signalling during peripheral T-cell activation and differentiation. Nat Rev Immunol 7(1):64–75. CrossRefPubMedGoogle Scholar
  167. Ottersbach K, Dzierzak E (2005) The murine placenta contains hematopoietic stem cells within the vascular labyrinth region. Dev Cell 8(3):377–387. CrossRefPubMedGoogle Scholar
  168. Owen AM, Herrod NJ, Menon DK, Clark JC, Downey SP, Carpenter TA, Minhas PS, Turkheimer FE, Williams EJ, Robbins TW, Sahakian BJ, Petrides M, Pickard JD (1999) Redefining the functional organization of working memory processes within human lateral prefrontal cortex. Eur J Neurosci 11(2):567–574CrossRefPubMedGoogle Scholar
  169. Owen MR, Sherratt JA, Wearing HJ (2000) Lateral induction by juxtacrine signaling is a new mechanism for pattern formation. Dev Biol 217(1):54–61. CrossRefPubMedGoogle Scholar
  170. Palis J, Robertson S, Kennedy M, Wall C, Keller G (1999) Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development 126(22):5073–5084PubMedGoogle Scholar
  171. Pan Y, Lin MH, Tian X, Cheng HT, Gridley T, Shen J, Kopan R (2004) gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell 7(5):731–743. CrossRefPubMedGoogle Scholar
  172. Park S, Lee C, Sabharwal P, Zhang M, Meyers CL, Sockanathan S (2013) GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK. Science 339(6117):324–328. CrossRefPubMedPubMedCentralGoogle Scholar
  173. Pasut A, Chang NC, Rodriguez UG, Faulkes S, Yin H, Lacaria M, Ming H, Rudnicki MA (2016) Notch Signaling Rescues Loss of Satellite Cells Lacking Pax7 and Promotes Brown Adipogenic Differentiation. Cell Rep 16(2):333–343. CrossRefPubMedPubMedCentralGoogle Scholar
  174. Pellegrinet L, Rodilla V, Liu Z, Chen S, Koch U, Espinosa L, Kaestner KH, Kopan R, Lewis J, Radtke F (2011) Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 140(4):1230–1240, e1231–1237. doi:
  175. Petrovic J, Formosa-Jordan P, Luna-Escalante JC, Abello G, Ibanes M, Neves J, Giraldez F (2014) Ligand-dependent Notch signaling strength orchestrates lateral induction and lateral inhibition in the developing inner ear. Development 141(11):2313–2324. CrossRefPubMedGoogle Scholar
  176. Pierfelice T, Alberi L, Gaiano N (2011) Notch in the vertebrate nervous system: an old dog with new tricks. Neuron 69(5):840–855. CrossRefPubMedGoogle Scholar
  177. Pin C, Watson AJ, Carding SR (2012) Modelling the spatio-temporal cell dynamics reveals novel insights on cell differentiation and proliferation in the small intestinal crypt. PLoS One 7(5):e37115. CrossRefPubMedPubMedCentralGoogle Scholar
  178. Pinto D, Gregorieff A, Begthel H, Clevers H (2003) Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 17(14):1709–1713. CrossRefPubMedPubMedCentralGoogle Scholar
  179. Poulos MG, Guo P, Kofler NM, Pinho S, Gutkin MC, Tikhonova A, Aifantis I, Frenette PS, Kitajewski J, Rafii S, Butler JM (2013) Endothelial Jagged-1 is necessary for homeostatic and regenerative hematopoiesis. Cell Rep 4(5):1022–1034. CrossRefPubMedPubMedCentralGoogle Scholar
  180. Radtke F, Wilson A, Stark G, Bauer M, van Meerwijk J, MacDonald HR, Aguet M (1999) Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10(5):547–558CrossRefPubMedGoogle Scholar
  181. Radtke F, Wilson A, Mancini SJ, MacDonald HR (2004) Notch regulation of lymphocyte development and function. Nat Immunol 5(3):247–253. CrossRefPubMedGoogle Scholar
  182. Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, Aster JC, Krishna S, Metzger D, Chambon P, Miele L, Aguet M, Radtke F, Dotto GP (2001) Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 20(13):3427–3436. CrossRefPubMedPubMedCentralGoogle Scholar
  183. Reedijk M, Odorcic S, Zhang H, Chetty R, Tennert C, Dickson BC, Lockwood G, Gallinger S, Egan SE (2008) Activation of Notch signaling in human colon adenocarcinoma. Int J Oncol 33(6):1223–1229PubMedPubMedCentralGoogle Scholar
  184. Relaix F, Marcelle C (2009) Muscle stem cells. Curr Opin Cell Biol 21(6):748–753. CrossRefPubMedGoogle Scholar
  185. Rhyu MS, Jan LY, Jan YN (1994) Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells. Cell 76(3):477–491CrossRefPubMedGoogle Scholar
  186. Riccio O, van Gijn ME, Bezdek AC, Pellegrinet L, van Es JH, Zimber-Strobl U, Strobl LJ, Honjo T, Clevers H, Radtke F (2008) Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep 9(4):377–383. CrossRefPubMedPubMedCentralGoogle Scholar
  187. Richard C, Drevon C, Canto PY, Villain G, Bollerot K, Lempereur A, Teillet MA, Vincent C, Rossello Castillo C, Torres M, Piwarzyk E, Speck NA, Souyri M, Jaffredo T (2013) Endothelio-mesenchymal interaction controls runx1 expression and modulates the notch pathway to initiate aortic hematopoiesis. Dev Cell 24(6):600–611. CrossRefPubMedPubMedCentralGoogle Scholar
  188. Robert-Moreno A, Espinosa L, de la Pompa JL, Bigas A (2005) RBPjkappa-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells. Development 132(5):1117–1126. CrossRefPubMedGoogle Scholar
  189. Robert-Moreno A, Espinosa L, Sanchez MJ, de la Pompa JL, Bigas A (2007) The notch pathway positively regulates programmed cell death during erythroid differentiation. Leukemia 21(7):1496–1503. CrossRefPubMedGoogle Scholar
  190. Robert-Moreno A, Guiu J, Ruiz-Herguido C, Lopez ME, Ingles-Esteve J, Riera L, Tipping A, Enver T, Dzierzak E, Gridley T, Espinosa L, Bigas A (2008) Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1. EMBO J 27(13):1886–1895. CrossRefPubMedPubMedCentralGoogle Scholar
  191. Rodilla V, Villanueva A, Obrador-Hevia A, Robert-Moreno A, Fernandez-Majada V, Grilli A, Lopez-Bigas N, Bellora N, Alba MM, Torres F, Dunach M, Sanjuan X, Gonzalez S, Gridley T, Capella G, Bigas A, Espinosa L (2009) Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc Natl Acad Sci U S A 106(15):6315–6320. CrossRefPubMedPubMedCentralGoogle Scholar
  192. Saito T, Chiba S, Ichikawa M, Kunisato A, Asai T, Shimizu K, Yamaguchi T, Yamamoto G, Seo S, Kumano K, Nakagami-Yamaguchi E, Hamada Y, Aizawa S, Hirai H (2003) Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity 18(5):675–685CrossRefPubMedGoogle Scholar
  193. Sakamoto M, Hirata H, Ohtsuka T, Bessho Y, Kageyama R (2003) The basic helix-loop-helix genes Hesr1/Hey1 and Hesr2/Hey2 regulate maintenance of neural precursor cells in the brain. J Biol Chem 278(45):44808–44815. CrossRefPubMedGoogle Scholar
  194. Sambasivan R, Yao R, Kissenpfennig A, Van Wittenberghe L, Paldi A, Gayraud-Morel B, Guenou H, Malissen B, Tajbakhsh S, Galy A (2011) Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development 138(17):3647–3656. CrossRefPubMedGoogle Scholar
  195. Sancho R, Blake SM, Tendeng C, Clurman BE, Lewis J, Behrens A (2013) Fbw7 repression by hes5 creates a feedback loop that modulates Notch-mediated intestinal and neural stem cell fate decisions. PLoS Biol 11(6):e1001586. CrossRefPubMedPubMedCentralGoogle Scholar
  196. Sander GR, Powell BC (2004) Expression of notch receptors and ligands in the adult gut. J Histochem Cytochem 52(4):509–516. CrossRefPubMedGoogle Scholar
  197. Sasaki N, Sachs N, Wiebrands K, Ellenbroek SI, Fumagalli A, Lyubimova A, Begthel H, van den Born M, van Es JH, Karthaus WR, Li VS, Lopez-Iglesias C, Peters PJ, van Rheenen J, van Oudenaarden A, Clevers H (2016) Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon. Proc Natl Acad Sci U S A 113(37):E5399–E5407. CrossRefPubMedPubMedCentralGoogle Scholar
  198. Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG, van den Born M, Barker N, Shroyer NF, van de Wetering M, Clevers H (2011) Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469(7330):415–418. CrossRefPubMedGoogle Scholar
  199. Schroeder T, Kohlhof H, Rieber N, Just U (2003) Notch signaling induces multilineage myeloid differentiation and up-regulates PU.1 expression. J Immunol 170(11):5538–5548CrossRefPubMedGoogle Scholar
  200. Schroeder T, Meier-Stiegen F, Schwanbeck R, Eilken H, Nishikawa S, Hasler R, Schreiber S, Bornkamm GW, Just U (2006) Activated Notch1 alters differentiation of embryonic stem cells into mesodermal cell lineages at multiple stages of development. Mech Dev 123(7):570–579. CrossRefPubMedGoogle Scholar
  201. Schuster-Gossler K, Cordes R, Gossler A (2007) Premature myogenic differentiation and depletion of progenitor cells cause severe muscle hypotrophy in Delta1 mutants. Proc Natl Acad Sci U S A 104(2):537–542. CrossRefPubMedGoogle Scholar
  202. Servian-Morilla E, Takeuchi H, Lee TV, Clarimon J, Mavillard F, Area-Gomez E, Rivas E, Nieto-Gonzalez JL, Rivero MC, Cabrera-Serrano M, Gomez-Sanchez L, Martinez-Lopez JA, Estrada B, Marquez C, Morgado Y, Suarez-Calvet X, Pita G, Bigot A, Gallardo E, Fernandez-Chacon R, Hirano M, Haltiwanger RS, Jafar-Nejad H, Paradas C (2016) A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss. EMBO Mol Med 8(11):1289–1309. CrossRefPubMedPubMedCentralGoogle Scholar
  203. Shimojo H, Ohtsuka T, Kageyama R (2008) Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron 58(1):52–64. CrossRefPubMedGoogle Scholar
  204. Shimojo H, Isomura A, Ohtsuka T, Kori H, Miyachi H, Kageyama R (2016) Oscillatory control of Delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis. Genes Dev 30(1):102–116. CrossRefPubMedPubMedCentralGoogle Scholar
  205. Shroyer NF, Helmrath MA, Wang VY, Antalffy B, Henning SJ, Zoghbi HY (2007) Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology 132(7):2478–2488. CrossRefPubMedGoogle Scholar
  206. Simpson P (1990) Lateral inhibition and the development of the sensory bristles of the adult peripheral nervous system of Drosophila. Development 109(3):509–519PubMedGoogle Scholar
  207. Sirakov M, Boussouar A, Kress E, Frau C, Lone IN, Nadjar J, Angelov D, Plateroti M (2015) The thyroid hormone nuclear receptor TRalpha1 controls the Notch signaling pathway and cell fate in murine intestine. Development 142(16):2764–2774. CrossRefPubMedGoogle Scholar
  208. Snippert HJ, van der Flier LG, Sato T, van Es JH, van den Born M, Kroon-Veenboer C, Barker N, Klein AM, van Rheenen J, Simons BD, Clevers H (2010) Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143(1):134–144. CrossRefPubMedGoogle Scholar
  209. Souilhol C, Lendinez JG, Rybtsov S, Murphy F, Wilson H, Hills D, Batsivari A, Binagui-Casas A, McGarvey AC, MacDonald HR, Kageyama R, Siebel C, Zhao S, Medvinsky A (2016) Developing HSCs become Notch independent by the end of maturation in the AGM region. Blood 128(12):1567–1577. CrossRefPubMedPubMedCentralGoogle Scholar
  210. Sprinzak D, Lakhanpal A, Lebon L, Santat LA, Fontes ME, Anderson GA, Garcia-Ojalvo J, Elowitz MB (2010) Cis-interactions between Notch and Delta generate mutually exclusive signalling states. Nature 465(7294):86–90. CrossRefPubMedPubMedCentralGoogle Scholar
  211. Stanger BZ, Datar R, Murtaugh LC, Melton DA (2005) Direct regulation of intestinal fate by Notch. Proc Natl Acad Sci U S A 102(35):12443–12448. CrossRefPubMedPubMedCentralGoogle Scholar
  212. 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):153–159CrossRefPubMedGoogle Scholar
  213. Tadeu AM, Horsley V (2013) Notch signaling represses p63 expression in the developing surface ectoderm. Development 140(18):3777–3786. CrossRefPubMedPubMedCentralGoogle Scholar
  214. Takada Y, Fukuda A, Chiba T, Seno H (2016) Brg1 plays an essential role in development and homeostasis of the duodenum through regulation of Notch signaling. Development 143(19):3532–3539. CrossRefPubMedGoogle Scholar
  215. Tian H, Biehs B, Chiu C, Siebel CW, Wu Y, Costa M, de Sauvage FJ, Klein OD (2015) Opposing activities of Notch and Wnt signaling regulate intestinal stem cells and gut homeostasis. Cell Rep 11(1):33–42. CrossRefPubMedPubMedCentralGoogle Scholar
  216. Tiberi L, van den Ameele J, Dimidschstein J, Piccirilli J, Gall D, Herpoel A, Bilheu A, Bonnefont J, Iacovino M, Kyba M, Bouschet T, Vanderhaeghen P (2012) BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets. Nat Neurosci 15(12):1627–1635. CrossRefPubMedGoogle Scholar
  217. Tozer S, Baek C, Fischer E, Goiame R, Morin X (2017) Differential routing of Mindbomb1 via centriolar satellites regulates asymmetric divisions of neural progenitors. Neuron 93(3):542–551. e544. CrossRefPubMedGoogle Scholar
  218. Ueo T, Imayoshi I, Kobayashi T, Ohtsuka T, Seno H, Nakase H, Chiba T, Kageyama R (2012) The role of Hes genes in intestinal development, homeostasis and tumor formation. Development 139(6):1071–1082. CrossRefPubMedGoogle Scholar
  219. van der Flier LG, Clevers H (2009) Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 71:241–260. CrossRefPubMedGoogle Scholar
  220. van Es JH, Sato T, van de Wetering M, Lyubimova A, Nee AN, Gregorieff A, Sasaki N, Zeinstra L, van den Born M, Korving J, Martens AC, Barker N, van Oudenaarden A, Clevers H (2012) Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 14(10):1099–1104. CrossRefPubMedPubMedCentralGoogle Scholar
  221. VanDussen KL, Samuelson LC (2010) Mouse atonal homolog 1 directs intestinal progenitors to secretory cell rather than absorptive cell fate. Dev Biol 346(2):215–223. CrossRefPubMedPubMedCentralGoogle Scholar
  222. VanDussen KL, Carulli AJ, Keeley TM, Patel SR, Puthoff BJ, Magness ST, Tran IT, Maillard I, Siebel C, Kolterud A, Grosse AS, Gumucio DL, Ernst SA, Tsai YH, Dempsey PJ, Samuelson LC (2012) Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development 139(3):488–497. CrossRefPubMedPubMedCentralGoogle Scholar
  223. Varnum-Finney B, Purton LE, Yu M, Brashem-Stein C, Flowers D, Staats S, Moore KA, Le Roux I, Mann R, Gray G, Artavanis-Tsakonas S, Bernstein ID (1998) The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells. Blood 91(11):4084–4091PubMedPubMedCentralGoogle Scholar
  224. Vasyutina E, Lenhard DC, Wende H, Erdmann B, Epstein JA, Birchmeier C (2007) RBP-J (Rbpsuh) is essential to maintain muscle progenitor cells and to generate satellite cells. Proc Natl Acad Sci U S A 104(11):4443–4448. CrossRefPubMedPubMedCentralGoogle Scholar
  225. Vieira NM, Elvers I, Alexander MS, Moreira YB, Eran A, Gomes JP, Marshall JL, Karlsson EK, Verjovski-Almeida S, Lindblad-Toh K, Kunkel LM, Zatz M (2015) Jagged 1 rescues the duchenne muscular dystrophy phenotype. Cell 163(5):1204–1213. CrossRefPubMedPubMedCentralGoogle Scholar
  226. Vooijs M, Ong CT, Hadland B, Huppert S, Liu Z, Korving J, van den Born M, Stappenbeck T, Wu Y, Clevers H, Kopan R (2007) Mapping the consequence of Notch1 proteolysis in vivo with NIP-CRE. Development 134(3):535–544. CrossRefPubMedPubMedCentralGoogle Scholar
  227. Walker EM, Thompson CA, Battle MA (2014) GATA4 and GATA6 regulate intestinal epithelial cytodifferentiation during development. Dev Biol 392(2):283–294. CrossRefPubMedPubMedCentralGoogle Scholar
  228. Wang W, Zimmerman G, Huang X, Yu S, Myers J, Wang Y, Moreton S, Nthale J, Awadallah A, Beck R, Xin W, Wald D, Huang AY, Zhou L (2016) Aberrant Notch signaling in the bone marrow microenvironment of acute lymphoid leukemia suppresses osteoblast-mediated support of hematopoietic niche function. Cancer Res 76(6):1641–1652. CrossRefPubMedPubMedCentralGoogle Scholar
  229. Watt FM, Estrach S, Ambler CA (2008) Epidermal Notch signalling: differentiation, cancer and adhesion. Curr Opin Cell Biol 20(2):171–179. CrossRefPubMedPubMedCentralGoogle Scholar
  230. Wearing HJ, Sherratt JA (2000) Keratinocyte growth factor signalling: a mathematical model of dermal-epidermal interaction in epidermal wound healing. Math Biosci 165(1):41–62CrossRefPubMedGoogle Scholar
  231. Wen Y, Bi P, Liu W, Asakura A, Keller C, Kuang S (2012) Constitutive Notch activation upregulates Pax7 and promotes the self-renewal of skeletal muscle satellite cells. Mol Cell Biol 32(12):2300–2311. CrossRefPubMedPubMedCentralGoogle Scholar
  232. Williams SE, Beronja S, Pasolli HA, Fuchs E (2011) Asymmetric cell divisions promote Notch-dependent epidermal differentiation. Nature 470(7334):353–358. CrossRefPubMedPubMedCentralGoogle Scholar
  233. Wilson A, MacDonald HR, Radtke F (2001) Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus. J Exp Med 194(7):1003–1012CrossRefPubMedPubMedCentralGoogle Scholar
  234. Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY (2001) Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294(5549):2155–2158. CrossRefPubMedGoogle Scholar
  235. Yaron A, Sprinzak D (2012) The cis side of juxtacrine signaling: a new role in the development of the nervous system. Trends Neurosci 35(4):230–239. CrossRefPubMedGoogle Scholar
  236. Yoon K, Gaiano N (2005) Notch signaling in the mammalian central nervous system: insights from mouse mutants. Nat Neurosci 8(6):709–715. CrossRefPubMedGoogle Scholar
  237. Yoon KJ, Koo BK, Im SK, Jeong HW, Ghim J, Kwon MC, Moon JS, Miyata T, Kong YY (2008) Mind bomb 1-expressing intermediate progenitors generate notch signaling to maintain radial glial cells. Neuron 58(4):519–531. CrossRefPubMedGoogle Scholar
  238. Yu X, Zou J, Ye Z, Hammond H, Chen G, Tokunaga A, Mali P, Li YM, Civin C, Gaiano N, Cheng L (2008) Notch signaling activation in human embryonic stem cells is required for embryonic, but not trophoblastic, lineage commitment. Cell Stem Cell 2(5):461–471. CrossRefPubMedPubMedCentralGoogle Scholar
  239. Yu VW, Saez B, Cook C, Lotinun S, Pardo-Saganta A, Wang YH, Lymperi S, Ferraro F, Raaijmakers MH, Wu JY, Zhou L, Rajagopal J, Kronenberg HM, Baron R, Scadden DT (2015) Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. J Exp Med 212(5):759–774. CrossRefPubMedPubMedCentralGoogle Scholar
  240. Yue F, Bi P, Wang C, Shan T, Nie Y, Ratliff TL, Gavin TP, Kuang S (2017) Pten is necessary for the quiescence and maintenance of adult muscle stem cells. Nat Commun 8:14328. CrossRefPubMedPubMedCentralGoogle Scholar
  241. Zalc A, Hayashi S, Aurade F, Brohl D, Chang T, Mademtzoglou D, Mourikis P, Yao Z, Cao Y, Birchmeier C, Relaix F (2014) Antagonistic regulation of p57kip2 by Hes/Hey downstream of Notch signaling and muscle regulatory factors regulates skeletal muscle growth arrest. Development 141(14):2780–2790. CrossRefPubMedGoogle Scholar
  242. Zhang P, He Q, Chen D, Liu W, Wang L, Zhang C, Ma D, Li W, Liu B, Liu F (2015) G protein-coupled receptor 183 facilitates endothelial-to-hematopoietic transition via Notch1 inhibition. Cell Res 25(10):1093–1107. CrossRefPubMedPubMedCentralGoogle Scholar
  243. Zhong W, Chia W (2008) Neurogenesis and asymmetric cell division. Curr Opin Neurobiol 18(1):4–11. CrossRefPubMedGoogle Scholar
  244. Zhong W, Feder JN, Jiang MM, Jan LY, Jan YN (1996) Asymmetric localization of a mammalian numb homolog during mouse cortical neurogenesis. Neuron 17(1):43–53CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Program in Cancer ResearchInstitut Hospital del Mar d’Investigacions Mèdiques (IMIM)BarcelonaSpain
  2. 2.Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)BarcelonaSpain

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