Regulation of Proneural Wave Propagation Through a Combination of Notch-Mediated Lateral Inhibition and EGF-Mediated Reaction Diffusion

  • Makoto SatoEmail author
  • Tetsuo Yasugi
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1218)


Notch-mediated lateral inhibition regulates binary cell fate choice, resulting in salt-and-pepper pattern formation during various biological processes. In many cases, Notch signaling acts together with other signaling systems. However, it is not clear what happens when Notch signaling is combined with other signaling systems. Mathematical modeling and the use of a simple biological model system will be essential to address this uncertainty. A wave of differentiation in the Drosophila visual center, the “proneural wave,” accompanies the activity of the Notch and EGF signaling pathways. Although all of the Notch signaling components required for lateral inhibition are involved in the proneural wave, no salt-and-pepper pattern is found during the progression of the proneural wave. Instead, Notch is activated along the wave front and regulates proneural wave progression. How does Notch signaling control wave propagation without forming a salt-and-pepper pattern? A mathematical model of the proneural wave, based on biological evidence, has demonstrated that Notch-mediated lateral inhibition is implemented within the proneural wave and that the diffusible action of EGF cancels salt-and-pepper pattern formation. The results from numerical simulation have been confirmed by genetic experiments in vivo and suggest that the combination of Notch-mediated lateral inhibition and EGF-mediated reaction diffusion enables a novel function of Notch signaling that regulates propagation of the proneural wave. Similar mechanisms may play important roles in diverse biological processes found in animal development and cancer pathogenesis.


Notch Delta Lateral inhibition EGF Reaction diffusion JAK/STAT Noise resistance Drosophila Visual system Proneural wave Mathematical model 



We thank Masaharu Nagayama and Yoshitaro Tanaka for their critical comments. This work was supported by Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Agency (JST) (Grant JPMJCR14D3 to M.S.); Grants-in-Aid for Scientific Research on Innovative Areas and Grants-in-Aid for Scientific Research (B) and (C) from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) (Grants JP17H05739, JP17H05761, JP17H03542, and JP19H04771 to M.S.; and Grants JP18H05099, 19K06674, and 19H04956 to T.Y.); Takeda Science Foundation (to M.S. and T.Y.); and a Grant for Cooperative Research on ‘Network Joint Research Center for Materials and Devices’ (to M.S.).


  1. Aguirre A, Rubio ME, Gallo V (2010) Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature 467(7313):323–327PubMedPubMedCentralCrossRefGoogle Scholar
  2. Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284(5415):770–776PubMedCrossRefPubMedCentralGoogle Scholar
  3. Baker NE, Yu SY (1997) Proneural function of neurogenic genes in the developing Drosophila eye. Curr Biol 7(2):122–132PubMedCrossRefPubMedCentralGoogle Scholar
  4. Baker AT, Zlobin A, Osipo C (2014) Notch-EGFR/HER2 bidirectional crosstalk in breast cancer. Front Oncol 4:360PubMedPubMedCentralCrossRefGoogle Scholar
  5. Baonza A, Freeman M (2001) Notch signalling and the initiation of neural development in the Drosophila eye. Development 128(20):3889–3898PubMedPubMedCentralGoogle Scholar
  6. Cabrera CV, Alonso MC (1991) Transcriptional activation by heterodimers of the achaete-scute and daughterless gene products of Drosophila. EMBO J 10(10):2965–2973PubMedPubMedCentralCrossRefGoogle Scholar
  7. Collier JR, Monk NA, Maini PK, Lewis JH (1996) Pattern formation by lateral inhibition with feedback: a mathematical model of delta-notch intercellular signalling. J Theor Biol 183(4):429–446PubMedCrossRefGoogle Scholar
  8. Corson F, Couturier L, Rouault H, Mazouni K, Schweisguth F (2017) Self-organized Notch dynamics generate stereotyped sensory organ patterns in Drosophila. Science 356(6337):eaai7407PubMedCrossRefPubMedCentralGoogle Scholar
  9. del Alamo D, Rouault H, Schweisguth F (2011) Mechanism and significance of cis-inhibition in Notch signalling. Curr Biol 21(1):R40–R47PubMedCrossRefGoogle Scholar
  10. Doroquez DB, Rebay I (2006) Signal integration during development: mechanisms of EGFR and Notch pathway function and cross-talk. Crit Rev Biochem Mol Biol 41(6):339–385PubMedCrossRefPubMedCentralGoogle Scholar
  11. Dutt A, Canevascini S, Froehli-Hoier E, Hajnal A (2004) EGF signal propagation during C. elegans vulval development mediated by ROM-1 rhomboid. PLoS Biol 2(11):e334PubMedPubMedCentralCrossRefGoogle Scholar
  12. Egger B, Boone JQ, Stevens NR, Brand AH, Doe CQ (2007) Regulation of spindle orientation and neural stem cell fate in the Drosophila optic lobe. Neural Dev 2:1PubMedPubMedCentralCrossRefGoogle Scholar
  13. Formosa-Jordan P, Ibanes M, Ares S, Frade JM (2012) Regulation of neuronal differentiation at the neurogenic wavefront. Development 139(13):2321–2329PubMedCrossRefPubMedCentralGoogle Scholar
  14. Freeman M (1996) Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye. Cell 87(4):651–660PubMedCrossRefPubMedCentralGoogle Scholar
  15. Ghysen A, Dambly-Chaudiere C, Jan LY, Jan YN (1993) Cell interactions and gene interactions in peripheral neurogenesis. Genes Dev 7(5):723–733PubMedCrossRefPubMedCentralGoogle Scholar
  16. Heberlein U, Wolff T, Rubin GM (1993) The TGF beta homolog dpp and the segment polarity gene hedgehog are required for propagation of a morphogenetic wave in the Drosophila retina. Cell 75(5):913–926PubMedCrossRefPubMedCentralGoogle Scholar
  17. 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):1203–1208PubMedCrossRefPubMedCentralGoogle Scholar
  18. Jarman AP, Grau Y, Jan LY, Jan YN (1993) atonal is a proneural gene that directs chordotonal organ formation in the Drosophila peripheral nervous system. Cell 73(7):1307–1321PubMedCrossRefPubMedCentralGoogle Scholar
  19. Jarman AP, Grell EH, Ackerman L, Jan LY, Jan YN (1994) Atonal is the proneural gene for Drosophila photoreceptors. Nature 369(6479):398–400PubMedCrossRefPubMedCentralGoogle Scholar
  20. Jorg DJ, Caygill EE, Hakes AE, Contreras EG, Brand AH, Simons BD (2019) The proneural wave in the Drosophila optic lobe is driven by an excitable reaction-diffusion mechanism. eLife 8:e40919PubMedPubMedCentralCrossRefGoogle Scholar
  21. Kageyama R, Niwa Y, Isomura A, Gonzalez A, Harima Y (2012) Oscillatory gene expression and somitogenesis. Wiley Interdiscip Rev Dev Biol 1(5):629–641PubMedCrossRefGoogle Scholar
  22. Kawamori H, Tai M, Sato M, Yasugi T, Tabata T (2011) Fat/Hippo pathway regulates the progress of neural differentiation signaling in the Drosophila optic lobe. Dev Growth Differ 53(5):653–667PubMedCrossRefGoogle Scholar
  23. Kulesa PM, Schnell S, Rudloff S, Baker RE, Maini PK (2007) From segment to somite: segmentation to epithelialization analyzed within quantitative frameworks. Dev Dyn 236(6):1392–1402PubMedPubMedCentralCrossRefGoogle Scholar
  24. Kunisch M, Haenlin M, Campos-Ortega JA (1994) Lateral inhibition mediated by the Drosophila neurogenic gene delta is enhanced by proneural proteins. Proc Natl Acad Sci U S A 91(21):10139–10143PubMedPubMedCentralCrossRefGoogle Scholar
  25. Li X, Erclik T, Bertet C, Chen Z, Voutev R, Venkatesh S, Morante J, Celik A, Desplan C (2013) Temporal patterning of Drosophila medulla neuroblasts controls neural fates. Nature 498(7455):456–462PubMedPubMedCentralCrossRefGoogle Scholar
  26. Lubensky DK, Pennington MW, Shraiman BI, Baker NE (2011) A dynamical model of ommatidial crystal formation. Proc Natl Acad Sci U S A 108(27):11145–11150PubMedPubMedCentralCrossRefGoogle Scholar
  27. Ma C, Zhou Y, Beachy PA, Moses K (1993) The segment polarity gene hedgehog is required for progression of the morphogenetic furrow in the developing Drosophila eye. Cell 75(5):927–938PubMedCrossRefGoogle Scholar
  28. Neumann CJ, Nuesslein-Volhard C (2000) Patterning of the zebrafish retina by a wave of sonic hedgehog activity. Science 289(5487):2137–2139PubMedCrossRefGoogle Scholar
  29. Orihara-Ono M, Toriya M, Nakao K, Okano H (2011) Downregulation of Notch mediates the seamless transition of individual Drosophila neuroepithelial progenitors into optic medullar neuroblasts during prolonged G1. Dev Biol 351(1):163–175PubMedCrossRefGoogle Scholar
  30. Pancewicz-Wojtkiewicz J (2016) Epidermal growth factor receptor and notch signaling in non-small-cell lung cancer. Cancer Med 5(12):3572–3578PubMedPubMedCentralCrossRefGoogle Scholar
  31. Pennington MW, Lubensky DK (2010) Switch and template pattern formation in a discrete reaction-diffusion system inspired by the Drosophila eye. Eur Phys J E Soft Matter 33(2):129–148PubMedPubMedCentralCrossRefGoogle Scholar
  32. Reddy BV, Rauskolb C, Irvine KD (2010) Influence of fat-hippo and notch signaling on the proliferation and differentiation of Drosophila optic neuroepithelia. Development 137(14):2397–2408PubMedPubMedCentralCrossRefGoogle Scholar
  33. Sato M, Suzuki T, Nakai Y (2013) Waves of differentiation in the fly visual system. Dev Biol 380(1):1–11PubMedCrossRefPubMedCentralGoogle Scholar
  34. Sato M, Yasugi T, Minami Y, Miura T, Nagayama M (2016) Notch-mediated lateral inhibition regulates proneural wave propagation when combined with EGF-mediated reaction diffusion. Proc Natl Acad Sci U S A 113(35):E5153–E5162PubMedPubMedCentralCrossRefGoogle Scholar
  35. Simpson P (1990) Lateral inhibition and the development of the sensory bristles of the adult peripheral nervous system of Drosophila. Development 109(3):509–519PubMedPubMedCentralGoogle Scholar
  36. 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):86–90PubMedPubMedCentralCrossRefGoogle Scholar
  37. Sundaram MV (2005) The love–hate relationship between Ras and Notch. Genes Dev 19(16):1825–1839PubMedCrossRefPubMedCentralGoogle Scholar
  38. Suzuki T, Kaido M, Takayama R, Sato M (2013) A temporal mechanism that produces neuronal diversity in the Drosophila visual center. Dev Biol 380(1):12–24PubMedCrossRefPubMedCentralGoogle Scholar
  39. Tanaka Y, Yasugi T, Nagayama M, Sato M, Ei SI (2018) JAK/STAT guarantees robust neural stem cell differentiation by shutting off biological noise. Sci Rep 8(1):12484PubMedPubMedCentralCrossRefGoogle Scholar
  40. Urban S, Lee JR, Freeman M (2001) Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107(2):173–182PubMedCrossRefGoogle Scholar
  41. Yang HJ, Silva AO, Koyano-Nakagawa N, McLoon SC (2009) Progenitor cell maturation in the developing vertebrate retina. Dev Dyn 238(11):2823–2836PubMedCrossRefGoogle Scholar
  42. Yasugi T, Umetsu D, Murakami S, Sato M, Tabata T (2008) Drosophila optic lobe neuroblasts triggered by a wave of proneural gene expression that is negatively regulated by JAK/STAT. Development 135:1471–1480PubMedCrossRefGoogle Scholar
  43. Yasugi T, Sugie A, Umetsu D, Tabata T (2010) Coordinated sequential action of EGFR and Notch signaling pathways regulates proneural wave progression in the Drosophila optic lobe. Development 137(19):3193–3203PubMedCrossRefGoogle Scholar
  44. Yuan Z, Praxenthaler H, Tabaja N, Torella R, Preiss A, Maier D, Kovall RA (2016) Structure and function of the Su(H)-Hairless repressor complex, the major antagonist of Notch signaling in Drosophila melanogaster. PLoS Biol 14(7):e1002509PubMedPubMedCentralCrossRefGoogle Scholar
  45. zur Lage PI, Prentice DR, Holohan EE, Jarman AP (2003) The Drosophila proneural gene amos promotes olfactory sensillum formation and suppresses bristle formation. Development 130(19):4683–4693PubMedCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Mathematical Neuroscience Unit, Institute for Frontier Science InitiativeKanazawa UniversityKanazawa-shiJapan
  2. 2.Laboratory of Developmental Neurobiology, Graduate School of Medical SciencesKanazawa UniversityKanazawa-shiJapan

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