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Establishment of a Developmental Compartment Requires Interactions between Three Synergistic -regulatory Modules


The separation of cell populations into distinct functional units is essential for both vertebrate and invertebrate animal development. A classical paradigm for this phenomenon is the establishment of developmental compartments during Drosophila wing development. These compartments depend on the restricted expression of two selector genes, engrailed in the posterior compartment and apterous (ap) in the dorsal compartment. Yet, despite the central role these genes and their restricted expression patterns play in Drosophila development, we still do not understand how these patterns are established or maintained. Here, by dissecting the regulatory sequences required for ap expression, we solve this problem for this critical selector gene. We used a combination of experimental approaches to identify and functionally characterize the cis-regulatory modules (CRMs) that regulate ap expression during Drosophila wing development. For these analyses we implement a novel technique allowing us to study the function of these CRMs in vivo, at the native ap locus. We found three ap CRMs crucial for wing development: the Early (apE) and the D/V (apDV) enhancers and the ap PRE (apP). Only when all three regulatory elements are combined is a uniform and complete ap expression domain generated. In summary, our results indicate that ap is regulated in time and space by a three-step mechanism that generates a lineage compartment by integrating input from separate CRMs for the initiation, refinement and maintenance of its expression.


Vyšlo v časopise: Establishment of a Developmental Compartment Requires Interactions between Three Synergistic -regulatory Modules. PLoS Genet 11(10): e32767. doi:10.1371/journal.pgen.1005376
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005376

Souhrn

The separation of cell populations into distinct functional units is essential for both vertebrate and invertebrate animal development. A classical paradigm for this phenomenon is the establishment of developmental compartments during Drosophila wing development. These compartments depend on the restricted expression of two selector genes, engrailed in the posterior compartment and apterous (ap) in the dorsal compartment. Yet, despite the central role these genes and their restricted expression patterns play in Drosophila development, we still do not understand how these patterns are established or maintained. Here, by dissecting the regulatory sequences required for ap expression, we solve this problem for this critical selector gene. We used a combination of experimental approaches to identify and functionally characterize the cis-regulatory modules (CRMs) that regulate ap expression during Drosophila wing development. For these analyses we implement a novel technique allowing us to study the function of these CRMs in vivo, at the native ap locus. We found three ap CRMs crucial for wing development: the Early (apE) and the D/V (apDV) enhancers and the ap PRE (apP). Only when all three regulatory elements are combined is a uniform and complete ap expression domain generated. In summary, our results indicate that ap is regulated in time and space by a three-step mechanism that generates a lineage compartment by integrating input from separate CRMs for the initiation, refinement and maintenance of its expression.


Zdroje

1. Irvine KD, Rauskolb C (2001) Boundaries in development: formation and function. Annu Rev Cell Dev Biol 17: 189–214. 11687488

2. Garcia-Bellido A, Ripoll P, Morata G (1976) Developmental compartmentalization in the dorsal mesothoracic disc of Drosophila. Dev Biol 48: 132–147. 1245256

3. Diaz-Benjumea FJ, Cohen SM (1995) Serrate signals through Notch to establish a Wingless-dependent organizer at the dorsal/ventral compartment boundary of the Drosophila wing. Development 121: 4215–4225. 8575321

4. Basler K, Struhl G (1994) Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 368: 208–214. 8145818

5. Nellen D, Burke R, Struhl G, Basler K (1996) Direct and long-range action of a DPP morphogen gradient. Cell 85: 357–368. 8616891

6. Zecca M, Basler K, Struhl G (1996) Direct and long-range action of a wingless morphogen gradient. Cell 87: 833–844. 8945511

7. Lecuit T, Brook WJ, Ng M, Calleja M, Sun H, et al. (1996) Two distinct mechanisms for long-range patterning by Decapentaplegic in the Drosophila wing. Nature 381: 387–393. 8632795

8. Neumann CJ, Cohen SM (1997) Long-range action of Wingless organizes the dorsal-ventral axis of the Drosophila wing. Development 124: 871–880. 9043068

9. Morata G, Lawrence PA (1975) Control of compartment development by the engrailed gene in Drosophila. Nature 255: 614–617. 1134551

10. Lawrence PA, Struhl G (1982) Further studies of the engrailed phenotype in Drosophila. EMBO J 1: 827–833. 6152896

11. Tabata T, Schwartz C, Gustavson E, Ali Z, Kornberg TB (1995) Creating a Drosophila wing de novo, the role of engrailed, and the compartment border hypothesis. Development 121: 3359–3369. 7588069

12. Zecca M, Basler K, Struhl G (1995) Sequential organizing activities of engrailed, hedgehog and decapentaplegic in the Drosophila wing. Development 121: 2265–2278. 7671794

13. Lawrence PA, Morata G (1976) Compartments in the wing of Drosophila: a study of the engrailed gene. Dev Biol 50: 321–337. 1278589

14. Blair SS, Brower DL, Thomas JB, Zavortink M (1994) The role of apterous in the control of dorsoventral compartmentalization and PS integrin gene expression in the developing wing of Drosophila. Development 120: 1805–1815. 7924988

15. Diaz-Benjumea FJ, Cohen SM (1993) Interaction between dorsal and ventral cells in the imaginal disc directs wing development in Drosophila. Cell 75: 741–752. 8242746

16. Cohen B, McGuffin ME, Pfeifle C, Segal D, Cohen SM (1992) apterous, a gene required for imaginal disc development in Drosophila encodes a member of the LIM family of developmental regulatory proteins. Genes Dev 6: 715–729. 1349545

17. Fernandez-Funez P, Lu CH, Rincon-Limas DE, Garcia-Bellido A, Botas J (1998) The relative expression amounts of apterous and its co-factor dLdb/Chip are critical for dorso-ventral compartmentalization in the Drosophila wing. EMBO J 17: 6846–6853. 9843490

18. Milan M, Cohen SM (1999) Regulation of LIM homeodomain activity in vivo: a tetramer of dLDB and apterous confers activity and capacity for regulation by dLMO. Mol Cell 4: 267–273. 10488342

19. van Meyel DJ, O'Keefe DD, Jurata LW, Thor S, Gill GN, et al. (1999) Chip and apterous physically interact to form a functional complex during Drosophila development. Mol Cell 4: 259–265. 10488341

20. Kim J, Sebring A, Esch JJ, Kraus ME, Vorwerk K, et al. (1996) Integration of positional signals and regulation of wing formation and identity by Drosophila vestigial gene. Nature 382: 133–138. 8700202

21. Rulifson EJ, Blair SS (1995) Notch regulates wingless expression and is not required for reception of the paracrine wingless signal during wing margin neurogenesis in Drosophila. Development 121: 2813–2824. 7555709

22. Spitz F, Furlong EE (2012) Transcription factors: from enhancer binding to developmental control. Nat Rev Genet 13: 613–626. doi: 10.1038/nrg3207 22868264

23. Capovilla M, Kambris Z, Botas J (2001) Direct regulation of the muscle-identity gene apterous by a Hox protein in the somatic mesoderm. Development 128: 1221–1230. 11262224

24. Lundgren SE, Callahan CA, Thor S, Thomas JB (1995) Control of neuronal pathway selection by the Drosophila LIM homeodomain gene apterous. Development 121: 1769–1773. 7600992

25. Bieli D, Kanca O, Gohl D, Denes A, Schedl P, et al. (2015) The Drosophila melanogaster Mutants apblot and apXasta Affect an Essential apterous Wing Enhancer. G3 5:1129–1143. doi: 10.1534/g3.115.017707 25840432

26. Wang SH, Simcox A, Campbell G (2000) Dual role for Drosophila epidermal growth factor receptor signaling in early wing disc development. Genes Dev 14: 2271–2276. 10995384

27. Zecca M, Struhl G (2002) Control of growth and patterning of the Drosophila wing imaginal disc by EGFR-mediated signaling. Development 129: 1369–1376. 11880346

28. Kassis JA, Brown JL (2013) Polycomb group response elements in Drosophila and vertebrates. Adv Genet 81: 83–118. doi: 10.1016/B978-0-12-407677-8.00003-8 23419717

29. Kennison JA (1995) The Polycomb and trithorax group proteins of Drosophila: trans-regulators of homeotic gene function. Annu Rev Genet 29: 289–303. 8825476

30. Oktaba K, Gutierrez L, Gagneur J, Girardot C, Sengupta AK, et al. (2008) Dynamic regulation by polycomb group protein complexes controls pattern formation and the cell cycle in Drosophila. Dev Cell 15: 877–889. doi: 10.1016/j.devcel.2008.10.005 18993116

31. Butler JE, Kadonaga JT (2002) The RNA polymerase II core promoter: a key component in the regulation of gene expression. Genes Dev 16: 2583–2592. 12381658

32. Negre N, Hennetin J, Sun LV, Lavrov S, Bellis M, et al. (2006) Chromosomal distribution of PcG proteins during Drosophila development. PLoS Biol 4: e170. 16613483

33. Tolhuis B, de Wit E, Muijrers I, Teunissen H, Talhout W, et al. (2006) Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster. Nat Genet 38: 694–699. 16628213

34. Schwartz YB, Kahn TG, Nix DA, Li XY, Bourgon R, et al. (2006) Genome-wide analysis of Polycomb targets in Drosophila melanogaster. Nat Genet 38: 700–705. 16732288

35. Gohl D, Muller M, Pirrotta V, Affolter M, Schedl P (2008) Enhancer blocking and transvection at the Drosophila apterous locus. Genetics 178: 127–143. doi: 10.1534/genetics.107.077768 18202363

36. Pekowska A, Benoukraf T, Zacarias-Cabeza J, Belhocine M, Koch F, et al. (2011) H3K4 tri-methylation provides an epigenetic signature of active enhancers. EMBO J 30: 4198–4210. doi: 10.1038/emboj.2011.295 21847099

37. Jory A, Estella C, Giorgianni MW, Slattery M, Laverty TR, et al. (2012) A survey of 6,300 genomic fragments for cis-regulatory activity in the imaginal discs of Drosophila melanogaster. Cell Rep 2: 1014–1024. doi: 10.1016/j.celrep.2012.09.010 23063361

38. Milan M, Diaz-Benjumea FJ, Cohen SM (1998) Beadex encodes an LMO protein that regulates Apterous LIM-homeodomain activity in Drosophila wing development: a model for LMO oncogene function. Genes Dev 12: 2912–2920. 9744867

39. Rebay I (2002) Keeping the receptor tyrosine kinase signaling pathway in check: lessons from Drosophila. Dev Biol 251: 1–17. 12413894

40. Halder G, Polaczyk P, Kraus ME, Hudson A, Kim J, et al. (1998) The Vestigial and Scalloped proteins act together to directly regulate wing-specific gene expression in Drosophila. Genes Dev 12: 3900–3909. 9869643

41. Pueyo JI, Galindo MI, Bishop SA, Couso JP (2000) Proximal-distal leg development in Drosophila requires the apterous gene and the Lim1 homologue dlim1. Development 127: 5391–5402. 11076760

42. Morris JR, Petrov DA, Lee AM, Wu CT (2004) Enhancer choice in cis and in trans in Drosophila melanogaster: role of the promoter. Genetics 167: 1739–1747. 15342512

43. Morris JR, Chen J, Filandrinos ST, Dunn RC, Fisk R, et al. (1999) An analysis of transvection at the yellow locus of Drosophila melanogaster. Genetics 151: 633–651. 9927457

44. Duncan IW (2002) Transvection effects in Drosophila. Annu Rev Genet 36: 521–556. 12429702

45. Dekker J, Rippe K, Dekker M, Kleckner N (2002) Capturing chromosome conformation. Science 295: 1306–1311. 11847345

46. Estella C, McKay DJ, Mann RS (2008) Molecular integration of wingless, decapentaplegic, and autoregulatory inputs into Distalless during Drosophila leg development. Dev Cell 14: 86–96. doi: 10.1016/j.devcel.2007.11.002 18194655

47. Struhl G, Basler K (1993) Organizing activity of wingless protein in Drosophila. Cell 72: 527–540. 8440019

48. Williams JA, Paddock SW, Carroll SB (1993) Pattern formation in a secondary field: a hierarchy of regulatory genes subdivides the developing Drosophila wing disc into discrete subregions. Development 117: 571–584. 8330528

49. Paul L, Wang SH, Manivannan SN, Bonanno L, Lewis S, et al. (2013) Dpp-induced Egfr signaling triggers postembryonic wing development in Drosophila. Proc Natl Acad Sci U S A 110: 5058–5063. doi: 10.1073/pnas.1217538110 23479629

50. Simcox AA, Grumbling G, Schnepp B, Bennington-Mathias C, Hersperger E, et al. (1996) Molecular, phenotypic, and expression analysis of vein, a gene required for growth of the Drosophila wing disc. Dev Biol 177: 475–489. 8806825

51. de Celis JF, Bray S (1997) Feed-back mechanisms affecting Notch activation at the dorsoventral boundary in the Drosophila wing. Development 124: 3241–3251. 9310319

52. Klein T, Arias AM (1998) Different spatial and temporal interactions between Notch, wingless, and vestigial specify proximal and distal pattern elements of the wing in Drosophila. Dev Biol 194: 196–212. 9501029

53. McKay DJ, Estella C, Mann RS (2009) The origins of the Drosophila leg revealed by the cis-regulatory architecture of the Distalless gene. Development 136: 61–71. doi: 10.1242/dev.029975 19036798

54. Crews ST, Pearson JC (2009) Transcriptional autoregulation in development. Curr Biol 19: R241–246. doi: 10.1016/j.cub.2009.01.015 19321138

55. DeVido SK, Kwon D, Brown JL, Kassis JA (2008) The role of Polycomb-group response elements in regulation of engrailed transcription in Drosophila. Development 135: 669–676. doi: 10.1242/dev.014779 18199580

56. Kwon D, Mucci D, Langlais KK, Americo JL, DeVido SK, et al. (2009) Enhancer-promoter communication at the Drosophila engrailed locus. Development 136: 3067–3075. doi: 10.1242/dev.036426 19675130

57. Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, et al. (2002) MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell 10: 1107–1117. 12453418

58. Poux S, Horard B, Sigrist CJ, Pirrotta V (2002) The Drosophila trithorax protein is a coactivator required to prevent re-establishment of polycomb silencing. Development 129: 2483–2493. 11973279

59. Klymenko T, Muller J (2004) The histone methyltransferases Trithorax and Ash1 prevent transcriptional silencing by Polycomb group proteins. EMBO Rep 5: 373–377. 15031712

60. Schuettengruber B, Ganapathi M, Leblanc B, Portoso M, Jaschek R, et al. (2009) Functional anatomy of polycomb and trithorax chromatin landscapes in Drosophila embryos. PLoS Biol 7: e13. doi: 10.1371/journal.pbio.1000013 19143474

61. Ghavi-Helm Y, Klein FA, Pakozdi T, Ciglar L, Noordermeer D, et al. (2014) Enhancer loops appear stable during development and are associated with paused polymerase. Nature 512: 96–100. doi: 10.1038/nature13417 25043061

62. Giorgianni MW, Mann RS (2011) Establishment of medial fates along the proximodistal axis of the Drosophila leg through direct activation of dachshund by Distalless. Dev Cell 20: 455–468. doi: 10.1016/j.devcel.2011.03.017 21497759

63. Perez L, Barrio L, Cano D, Fiuza UM, Muzzopappa M, et al. (2011) Enhancer-PRE communication contributes to the expansion of gene expression domains in proliferating primordia. Development 138: 3125–3134. doi: 10.1242/dev.065599 21715425

64. Bejarano F, Milan M (2009) Genetic and epigenetic mechanisms regulating hedgehog expression in the Drosophila wing. Dev Biol 327: 508–515. doi: 10.1016/j.ydbio.2009.01.006 19210960

65. Steffen PA, Ringrose L (2014) What are memories made of? How Polycomb and Trithorax proteins mediate epigenetic memory. Nat Rev Mol Cell Biol 15: 340–356. doi: 10.1038/nrm3789 24755934

66. Bischof J, Maeda RK, Hediger M, Karch F, Basler K (2007) An optimized transgenesis system for Drosophila using germ-line-specific phiC31 integrases. Proc Natl Acad Sci U S A 104: 3312–3317. 17360644

67. Caussinus E, Kanca O, Affolter M (2012) Fluorescent fusion protein knockout mediated by anti-GFP nanobody. Nat Struct Mol Biol 19: 117–121.

68. Siegal ML, Hartl DL (1996) Transgene Coplacement and high efficiency site-specific recombination with the Cre/loxP system in Drosophila. Genetics 144: 715–726. 8889532

69. Golic KG, Golic MM (1996) Engineering the Drosophila genome: chromosome rearrangements by design. Genetics 144: 1693–1711. 8978056

70. Venken KJ, Schulze KL, Haelterman NA, Pan H, He Y, et al. (2011) MiMIC: a highly versatile transposon insertion resource for engineering Drosophila melanogaster genes. Nat Methods 8: 737–743. 21985007

71. Sipos L, Kozma G, Molnar E, Bender W (2007) In situ dissection of a Polycomb response element in Drosophila melanogaster. Proc Natl Acad Sci U S A 104: 12416–12421. 17640916

72. Gloor GB, Nassif NA, Johnson-Schlitz DM, Preston CR, Engels WR (1991) Targeted gene replacement in Drosophila via P element-induced gap repair. Science 253: 1110–1117. 1653452

73. Bateman JR, Lee AM, Wu CT (2006) Site-specific transformation of Drosophila via phiC31 integrase-mediated cassette exchange. Genetics 173: 769–777. 16547094

74. Makarova O, Kamberov E, Margolis B (2000) Generation of deletion and point mutations with one primer in a single cloning step. Biotechniques 29: 970–972. 11084856

75. Greenspan R (1997) Fly pushing: The theory and practice of Drosophila genetics.

76. Weiss A, Charbonnier E, Ellertsdottir E, Tsirigos A, Wolf C, et al. (2010) A conserved activation element in BMP signaling during Drosophila development. Nat Struct Mol Biol 17: 69–76. doi: 10.1038/nsmb.1715 20010841

77. Boy AL, Zhai Z, Habring-Muller A, Kussler-Schneider Y, Kaspar P, et al. (2010) Vectors for efficient and high-throughput construction of fluorescent drosophila reporters using the PhiC31 site-specific integration system. Genesis 48: 452–456. doi: 10.1002/dvg.20637 20506180

78. Sosinsky A, Bonin CP, Mann RS, Honig B (2003) Target Explorer: An automated tool for the identification of new target genes for a specified set of transcription factors. Nucleic Acids Res 31: 3589–3592. 12824372

79. Slattery M, Voutev R, Ma L, Negre N, White KP, et al. (2013) Divergent transcriptional regulatory logic at the intersection of tissue growth and developmental patterning. PLoS Genet 9: e1003753. doi: 10.1371/journal.pgen.1003753 24039600

80. Teytelman L, Thurtle DM, Rine J, van Oudenaarden A (2013) Highly expressed loci are vulnerable to misleading ChIP localization of multiple unrelated proteins. Proc Natl Acad Sci U S A 110: 18602–18607. doi: 10.1073/pnas.1316064110 24173036

81. Webber JL, Zhang J, Mitchell-Dick A, Rebay I (2013) 3D chromatin interactions organize Yan chromatin occupancy and repression at the even-skipped locus. Genes Dev 27: 2293–2298.

82. Thibault ST, Singer MA, Miyazaki WY, Milash B, Dompe NA, et al. (2004) A complementary transposon tool kit for Drosophila melanogaster using P and piggyBac. Nat Genet 36: 283–287. 14981521

83. Moabbi AM, Agarwal N, El Kaderi B, Ansari A (2012) Role for gene looping in intron-mediated enhancement of transcription. Proc Natl Acad Sci U S A 109: 8505–8510. doi: 10.1073/pnas.1112400109 22586116

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