Negative Regulation for Neural Patterning in the Drosophila eye

  • Kwang-Wook ChoiEmail author


The Drosophila compound eye is a complex sensory system derived from retinal primordium called the eye imaginal disc. Differentiation of the retinal primordium into different cell types is a key to the visual function of the eye. The fly eye has a simple structure with only a few cell types and a precise organization with a repetitive pattern, thus serving as a favorable model for studying the genetic basis of retinal patterning. An important early event in retinal differentiation is the generation and assembly of neural precursor cells. A number of genes and multiple signaling pathways participate in this process. Many of these genes are involved in promoting the neural differentiation. However, retinal neurogenesis also requires a number of negative factors. Thus, early patterning in the eye is established by interactions between these yin–yang gene activities. This chapter will describe the function of these genetic factors, focusing more on negative regulators that help develop the precise pattern of the adult eye.


Epidermal Growth Factor Receptor Lateral Inhibition Epidermal Growth Factor Receptor Signaling Retinal Differentiation Morphogenetic Furrow 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Akimaru H, Saigo K (1991) DNA binding activity of the BarH1 homeodomain of Drosophila. Nucleic Acids Symp Ser (25):29–30Google Scholar
  2. Annaert W, De Strooper B (1999) Presenilins: molecular switches between proteolysis and signal transduction. Trends Neurosci 22:439–443PubMedCrossRefGoogle Scholar
  3. Baker NE, Firth LC (2011) Retinal determination genes function along with cell–cell signals to regulate Drosophila eye development: examples of multi-layered regulation by master regulators. Bioessays 33:538–546PubMedCrossRefGoogle Scholar
  4. Baker NE, Mlodzik M, Rubin GM (1990) Spacing differentiation in the developing Drosophila eye: a fibrinogen-related lateral inhibitor encoded by scabrous. Science 250:1370–1377PubMedCrossRefGoogle Scholar
  5. Baker NE, Rubin GM (1989) Effect on eye development of dominant mutations in Drosophila homologue of the EGF receptor. Nature 340:150–153PubMedCrossRefGoogle Scholar
  6. Baker NE, Yu SY (1997) Proneural function of neurogenic genes in the developing Drosophila eye. Curr Biol 7:122–132PubMedCrossRefGoogle Scholar
  7. Baonza A, Casci T, Freeman M (2001) A primary role for the epidermal growth factor receptor in ommatidial spacing in the Drosophila eye. Curr Biol 11:396–404PubMedCrossRefGoogle Scholar
  8. Baonza A, Freeman M (2001) Notch signalling and the initiation of neural development in the Drosophila eye. Development 128:3889–3898PubMedGoogle Scholar
  9. Beatus P, Lendahl U (1998) Notch and neurogenesis. J Neurosci Res 54:125–136PubMedCrossRefGoogle Scholar
  10. Bhattacharya A, Baker NE (2011) A network of broadly expressed HLH genes regulates tissue-specific cell fates. Cell 147:881–892PubMedCrossRefGoogle Scholar
  11. Bhattacharya A, Baker NE (2012) The Role of the bHLH Protein Hairy in Morphogenetic Furrow Progression in the Developing Drosophila Eye. PLoS One 7:e47503PubMedCrossRefGoogle Scholar
  12. Blair SS (1992) Engrailed expression in the anterior lineage compartment of the developing wing blade of Drosophila. Development 115:21–33PubMedGoogle Scholar
  13. Borod ER, Heberlein U (1998) Mutual regulation of decapentaplegic and hedgehog during the initiation of differentiation in the Drosophila retina. Dev Biol 197:187–197PubMedCrossRefGoogle Scholar
  14. Brown KE, Kerr M, Freeman M (2007) The EGFR ligands Spitz and Keren act cooperatively in the Drosophila eye. Dev Biol 307:105–113PubMedCrossRefGoogle Scholar
  15. Brown NL, Kanekar S, Vetter ML, Tucker PK, Gemza DL, Glaser T (1998) Math5 encodes a murine basic helix-loop-helix transcription factor expressed during early stages of retinal neurogenesis. Development 125:4821–4833PubMedGoogle Scholar
  16. Brown NL, Paddock SW, Sattler CA, Cronmiller C, Thomas BJ, Carroll SB (1996) daughterless is required for Drosophila photoreceptor cell determination, eye morphogenesis, and cell cycle progression. Dev Biol 179:65–78PubMedCrossRefGoogle Scholar
  17. Brown NL, Sattler CA, Paddock SW, Carroll SB (1995) Hairy and emc negatively regulate morphogenetic furrow progression in the Drosophila eye. Cell 80:879–887PubMedCrossRefGoogle Scholar
  18. Cabrera CV (1990) Lateral inhibition and cell fate during neurogenesis in Drosophila: the interactions between scute, Notch and Delta. Development 110:733–742PubMedGoogle Scholar
  19. Cagan RL, Ready DF (1989) Notch is required for successive cell decisions in the developing Drosophila retina. Genes Dev 3:1099–1112PubMedCrossRefGoogle Scholar
  20. Carrera I, Janody F, Leeds N, Duveau F, Treisman JE (2008) Pygopus activates Wingless target gene transcription through the mediator complex subunits Med12 and Med13. Proc Natl Acad Sci U S A 105:6644–6649PubMedCrossRefGoogle Scholar
  21. Caudy M, Grell EH, Dambly-Chaudiere C, Ghysen A, Jan LY, Jan YN (1988a) The maternal sex determination gene daughterless has zygotic activity necessary for the formation of peripheral neurons in Drosophila. Genes Dev 2:843–852CrossRefGoogle Scholar
  22. Caudy M, Vassin H, Brand M, Tuma R, Jan LY, Jan YN (1988b) daughterless, a Drosophila gene essential for both neurogenesis and sex determination, has sequence similarities to myc and the achaete-scute complex. Cell 55:1061–1067CrossRefGoogle Scholar
  23. Chanut F, Heberlein U (1997) Role of decapentaplegic in initiation and progression of the morphogenetic furrow in the developing Drosophila retina. Development 124:559–567PubMedGoogle Scholar
  24. Cho B, Fischer JA (2011) Ral GTPase promotes asymmetric Notch activation in the Drosophila eye in response to Frizzled/PCP signaling by repressing ligand-independent receptor activation. Development 138:1349–1359PubMedCrossRefGoogle Scholar
  25. Cho B, Fischer JA (2012) Ral inhibits ligand-independent Notch signaling in Drosophila. Small GTPases 3:186–191PubMedCrossRefGoogle Scholar
  26. Choi KW, Mozer B, Benzer S (1996) Independent determination of symmetry and polarity in the Drosophila eye. Proc Natl Acad Sci U S A 93:5737–5741PubMedCrossRefGoogle Scholar
  27. Cooper MT, Bray SJ (1999) Frizzled regulation of Notch signalling polarizes cell fate in the Drosophila eye. Nature 397:526–530PubMedCrossRefGoogle Scholar
  28. Cronmiller C, Schedl P, Cline TW (1988) Molecular characterization of daughterless, a Drosophila sex determination gene with multiple roles in development. Genes Dev 2:1666–1676PubMedCrossRefGoogle Scholar
  29. Cubas P, Celis JF de, Campuzano S, Modolell J (1991) Proneural clusters of achaete-scute expression and the generation of sensory organs in the Drosophila imaginal wing disc. Genes Dev 5:996–1008PubMedCrossRefGoogle Scholar
  30. Curtiss J, Mlodzik M (2000) Morphogenetic furrow initiation and progression during eye development in Drosophila: the roles of decapentaplegic, hedgehog and eyes absent. Development 127:1325–1336PubMedGoogle Scholar
  31. del Alamo D, Mlodzik M (2006) Frizzled/PCP-dependent asymmetric neuralized expression determines R3/R4 fates in the Drosophila eye. Dev Cell 11:887–894PubMedCrossRefGoogle Scholar
  32. Dokucu ME, Zipursky SL, Cagan RL (1996) Atonal, rough and the resolution of proneural clusters in the developing Drosophila retina. Development 122:139–4147Google Scholar
  33. Dominguez M, Hafen E (1997) Hedgehog directly controls initiation and propagation of retinal differentiation in the Drosophila eye. Genes Dev 11:3254–3264PubMedCrossRefGoogle Scholar
  34. Dominguez M, Wasserman JD, Freeman M (1998) Multiple functions of the EGF receptor in Drosophila eye development. Curr Biol 8:1039–1048PubMedCrossRefGoogle Scholar
  35. Ellis MC, Weber U, Wiersdorff V, Mlodzik M (1994) Confrontation of scabrous expressing and non-expressing cells is essential for normal ommatidial spacing in the Drosophila eye. Development 120:1959–1969PubMedGoogle Scholar
  36. Fanto M, Mlodzik M (1999) Asymmetric Notch activation specifies photoreceptors R3 and R4 and planar polarity in the Drosophila eye. Nature 397:523–526PubMedCrossRefGoogle Scholar
  37. Fetchko M, Huang W, Li Y, Lai ZC (2002) Drosophila Gp150 is required for early ommatidial development through modulation of Notch signaling. EMBO J 21:1074–1083PubMedCrossRefGoogle Scholar
  38. Frankfort BJ, Mardon G (2002) R8 development in the Drosophila eye: a paradigm for neural selection and differentiation. Development 129:1295–1306PubMedGoogle Scholar
  39. Freeman M (1994) The spitz gene is required for photoreceptor determination in the Drosophila eye where it interacts with the EGF receptor. Mech Dev 48:25–33PubMedCrossRefGoogle Scholar
  40. Fu W, Baker NE (2003) Deciphering synergistic and redundant roles of Hedgehog, Decapentaplegic and Delta that drive the wave of differentiation in Drosophila eye development. Development 130:5229–5239PubMedCrossRefGoogle Scholar
  41. Ghysen A, Dambly-Chaudiere C (1989) Genesis of the Drosophila peripheral nervous system. Trends Genet 5:251–255PubMedCrossRefGoogle Scholar
  42. Goulding SE, zur Lage P, Jarman AP (2000) amos, a proneural gene for Drosophila olfactory sense organs that is regulated by lozenge. Neuron 25:69–78PubMedCrossRefGoogle Scholar
  43. Greenwood S, Struhl G (1999) Progression of the morphogenetic furrow in the Drosophila eye: the roles of Hedgehog, Decapentaplegic and the Raf pathway. Development 126:5795–5808PubMedGoogle Scholar
  44. Halder G, Callaerts P, Gehring WJ (1995) Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science 267:1788–1792PubMedCrossRefGoogle Scholar
  45. Heberlein U, Moses K (1995) Mechanisms of Drosophila retinal morphogenesis: the virtues of being progressive. Cell 81:987–990PubMedCrossRefGoogle Scholar
  46. 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 75:913–926PubMedCrossRefGoogle Scholar
  47. Heitzler P, Simpson P (1991) The choice of cell fate in the epidermis of Drosophila. Cell 64:1083–1092PubMedCrossRefGoogle Scholar
  48. Higashijima S, Kojima T, Michiue T, Ishimaru S, Emori Y, Saigo K (1992) Dual Bar homeo box genes of Drosophila required in two photoreceptor cells, R1 and R6, and primary pigment cells for normal eye development. Genes Dev 6:50–60PubMedCrossRefGoogle Scholar
  49. Hsiung F, Moses K (2002) Retinal development in Drosophila: specifying the first neuron. Hum Mol Genet 11:1207–1214PubMedCrossRefGoogle Scholar
  50. Huang ML, Hsu CH, Chien CT (2000) The proneural gene amos promotes multiple dendritic neuron formation in the Drosophila peripheral nervous system. Neuron 25:57–67PubMedCrossRefGoogle Scholar
  51. Ito M, Roeder RG (2001) The TRAP/SMCC/Mediator complex and thyroid hormone receptor function. Trends Endocrinol Metab 12:127–134PubMedCrossRefGoogle Scholar
  52. Janody F, Treisman JE (2011) Requirements for mediator complex subunits distinguish three classes of notch target genes at the Drosophila wing margin Dev Dyn 240:2051–2059PubMedCrossRefGoogle Scholar
  53. Jarman AP, Grell EH, Ackerman L, Jan LY, Jan YN (1994) Atonal is the proneural gene for Drosophila photoreceptors. Nature 369:398–400PubMedCrossRefGoogle Scholar
  54. Kametaka S, Kametaka A, Yonekura S, Haruta M, Takenoshita S, Goto S, Waguri S (2012) AP-1 clathrin adaptor and CG8538/Aftiphilin are involved in Notch signaling during eye development in Drosophila melanogaster. J Cell Sci 125:634–648PubMedCrossRefGoogle Scholar
  55. Kimmel BE, Heberlein U, Rubin GM (1990) The homeo domain protein rough is expressed in a subset of cells in the developing Drosophila eye where it can specify photoreceptor cell subtype. Genes Dev 4:712–727PubMedCrossRefGoogle Scholar
  56. Kopan R, Goate A (2002) Aph-2/Nicastrin: an essential component of gamma-secretase and regulator of Notch signaling and Presenilin localization. Neuron 33:321–324PubMedCrossRefGoogle Scholar
  57. Kornberg T (1981) Engrailed: a gene controlling compartment and segment formation in Drosophila. Proc Natl Acad Sci U S A 78:1095–1099Google Scholar
  58. Kumar JP, Moses K (2001) EGF receptor and Notch signaling act upstream of Eyeless/Pax6 to control eye specification. Cell 104:687–697PubMedCrossRefGoogle Scholar
  59. Kumar JP, Tio M, Hsiung F, Akopyan S, Gabay L, Seger R, Shilo BZ, Moses K (1998) Dissecting the roles of the Drosophila EGF receptor in eye development and MAP kinase activation. Development 125:3875–3885PubMedGoogle Scholar
  60. Lai EC, Deblandre GA, Kintner C, Rubin GM (2001) Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta. Dev Cell 1:783–794PubMedCrossRefGoogle Scholar
  61. Li Y, Fetchko M, Lai ZC, Baker NE (2003) Scabrous and Gp150 are endosomal proteins that regulate Notch activity. Development 130:2819–2827PubMedCrossRefGoogle Scholar
  62. Lim J, Choi KW (2003) Bar homeodomain proteins are anti-proneural in the Drosophila eye: transcriptional repression of atonal by Bar prevents ectopic retinal neurogenesis. Development 130:5965–5974PubMedCrossRefGoogle Scholar
  63. Lim J, Choi KW (2004) Induction and autoregulation of the anti-proneural gene Bar during retinal neurogenesis in Drosophila. Development 131:5573–5580PubMedCrossRefGoogle Scholar
  64. Lim J, Jafar-Nejad H, Hsu YC, Choi KW (2008) Novel function of the class I bHLH protein Daughterless in the negative regulation of proneural gene expression in the Drosophila eye. EMBO Rep 9:1128–1133PubMedCrossRefGoogle Scholar
  65. Lim J, Lee OK, Hsu YC, Singh A, Choi KW (2007) Drosophila TRAP230/240 are essential coactivators for Atonal in retinal neurogenesis. Dev Biol 308:322–330PubMedCrossRefGoogle Scholar
  66. Malik S, Roeder RG (2000) Transcriptional regulation through Mediator-like coactivators in yeast and metazoan cells. Trends Biochem Sci 25:277–283PubMedCrossRefGoogle Scholar
  67. Melicharek D, Shah A, DiStefano G, Gangemi AJ, Orapallo A, Vrailas-Mortimer AD, Marenda DR (2008) Identification of novel regulators of atonal expression in the developing Drosophila retina. Genetics 180:2095–2110PubMedCrossRefGoogle Scholar
  68. Morata G, Lawrence PA (1975) Control of compartment development by the engrailed gene in Drosophila. Nature 255:614–617PubMedCrossRefGoogle Scholar
  69. Niwa N, Hiromi Y, Okabe M (2004) A conserved developmental program for sensory organ formation in Drosophila melanogaster. Nat Genet 36:293–297PubMedCrossRefGoogle Scholar
  70. Pavlopoulos E, Pitsouli C, Klueg KM, Muskavitch MA, Moschonas NK, Delidakis C (2001) Neuralized Encodes a peripheral membrane protein involved in delta signaling and endocytosis. Dev Cell 1:807–816PubMedCrossRefGoogle Scholar
  71. Pepple KL, Atkins M, Venken K, Wellnitz K, Harding M, Frankfort B, Mardon G (2008) Two-step selection of a single R8 photoreceptor: a bistable loop between senseless and rough locks in R8 fate. Development 135:4071–4079PubMedCrossRefGoogle Scholar
  72. Powell PA, Wesley C, Spencer S, Cagan RL (2001) Scabrous complexes with Notch to mediate boundary formation. Nature 409:626–630PubMedCrossRefGoogle Scholar
  73. Raftery LA, Sanicola M, Blackman RK, Gelbart WM (1991) The relationship of decapentaplegic and engrailed expression in Drosophila imaginal disks: do these genes mark the anterior–posterior compartment boundary?. Development 113:27–33PubMedGoogle Scholar
  74. Ready DF, Hanson TE, Benzer S (1976) Development of the Drosophila retina, a neurocrystalline lattice. Dev Biol 53:217–240PubMedCrossRefGoogle Scholar
  75. Rodrigues AB, Werner E, Moses K (2005) Genetic and biochemical analysis of the role of EGFR in the morphogenetic furrow of the developing Drosophila eye. Development 132:4697–4707PubMedCrossRefGoogle Scholar
  76. Roignant JY, Treisman JE (2009) Pattern formation in the Drosophila eye disc. Int J Dev Biol 53:795–804PubMedCrossRefGoogle Scholar
  77. Romani S, Campuzano S, Macagno ER, Modolell J (1989) Expression of achaete and scute genes in Drosophila imaginal discs and their function in sensory organ development. Genes Dev 3:997–1007PubMedCrossRefGoogle Scholar
  78. Rooke JE, Xu T (1998) Positive and negative signals between interacting cells for establishing neural fate. Bioessays 20:209–214PubMedCrossRefGoogle Scholar
  79. Rutledge BJ, Zhang K, Bier E, Jan YN, Perrimon N (1992) The Drosophila spitz gene encodes a putative EGF-like growth factor involved in dorsal–ventral axis formation and neurogenesis. Genes Dev 6:1503–1517PubMedCrossRefGoogle Scholar
  80. Sanicola M, Sekelsky J, Elson S, Gelbart WM (1995) Drawing a stripe in Drosophila imaginal disks: negative regulation of decapentaplegic and patched expression by engrailed. Genetics 139:745–756PubMedGoogle Scholar
  81. Schweitzer R, Howes R, Smith R, Shilo BZ, Freeman M (1995) Inhibition of Drosophila EGF receptor activation by the secreted protein Argos. Nature 376:699–702PubMedCrossRefGoogle Scholar
  82. Singh A, Tare M, Puli OR, Kango-Singh M (2012) A glimpse into dorso-ventral patterning of the Drosophila eye. Dev Dyn 241:69–84PubMedCrossRefGoogle Scholar
  83. Singh J, Mlodzik M (2012) Hibris, a Drosophila nephrin homolog, is required for presenilin-mediated Notch and APP-like cleavages. Dev Cell 23:82–96PubMedCrossRefGoogle Scholar
  84. Skeath JB, Carroll SB (1991) Regulation of achaete-scute gene expression and sensory organ pattern formation in the Drosophila wing. Genes Dev 5:984–995PubMedCrossRefGoogle Scholar
  85. Steinberg AG, Abramowitz M (1938) The Bar “Locus” and the v reaction in Drosophila melanogaster. Proc Natl Acad Sci U S A 24:107–111PubMedCrossRefGoogle Scholar
  86. Sun Y, Jan LY, Jan YN (1998) Transcriptional regulation of atonal during development of the Drosophila peripheral nervous system. Development 125:3731–3740PubMedGoogle Scholar
  87. Tanaka-Matakatsu M, Du W (2008) Direct control of the proneural gene atonal by retinal determination factors during Drosophila eye development. Dev Biol 313:787–801PubMedCrossRefGoogle Scholar
  88. Tomlinson A, Ready DF (1987) Neuronal differentiation in Drosophila ommatidium. Dev Biol 120:366–376PubMedCrossRefGoogle Scholar
  89. Tomlinson A, Struhl G (1999) Decoding vectorial information from a gradient: sequential roles of the receptors Frizzled and Notch in establishing planar polarity in the Drosophila eye. Development 126:5725–5738PubMedGoogle Scholar
  90. Treisman J (2001) Drosophila homologues of the transcriptional coactivation complex subunits TRAP240 and TRAP230 are required for identical processes in eye-antennal disc development. Development 128:603–615PubMedGoogle Scholar
  91. Treisman JE (2004) Coming to our senses. Bioessays 26:825–828PubMedCrossRefGoogle Scholar
  92. Weinmaster G, Fischer JA (2011) Notch ligand ubiquitylation: what is it good for?. Dev Cell 21:134–144PubMedCrossRefGoogle Scholar
  93. Wolff T, Ready DF (1991) The beginning of pattern formation in the Drosophila compound eye: the morphogenetic furrow and the second mitotic wave. Development 113:841–850PubMedGoogle Scholar
  94. Yang L, Baker NE (2001) Role of the EGFR/Ras/Raf pathway in specification of photoreceptor cells in the Drosophila retina. Development 128:1183–1191PubMedGoogle Scholar
  95. Ye Y, Lukinova N, Fortini ME (1999) Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature 398:525–529PubMedCrossRefGoogle Scholar
  96. Yeh E, Dermer M, Commisso C, Zhou L, McGlade CJ, Boulianne GL (2001) Neuralized functions as an E3 ubiquitin ligase during Drosophila development. Curr Biol 11:1675–1679PubMedCrossRefGoogle Scholar
  97. Zhang T, Ranade S, Cai CQ, Clouser C, Pignoni F (2006) Direct control of neurogenesis by selector factors in the fly eye: regulation of atonal by Ey and So. Development 133:4881–4889PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Biological SciencesKorea Advanced Institute of Science and TechnologyDaejeonRep. of Korea
  2. 2.Graduate School of Nanoscience and TechnologyKorea Advanced Institute of Science and TechnologyDaejeonRep. of Korea

Personalised recommendations