Organs develop from groups of undifferentiated cells that proliferate and differentiate into specific cell types. During development, the coupling between proliferation and differentiation programs ensures that enough cells of the different cell types are generated. This is critical for proper organ formation and function. Here, we use the developing Drosophila eye to examine how the coupling between these two programs is achieved. During eye development, progenitors are amplified before they exit the cell cycle and enter the differentiation program. This amplification step depends on an expression burst of the mitotic trigger string/cdc25, which, by forcing cells into mitosis, synchronizes cells in G1 just before differentiation onset. Thus string regulation acts as a hub where differentiation and proliferation programs are integrated. We identify a DNA element that controls the burst of string expression prior to differentiation, and show that it is regulated by the same gene network that triggers eye development. The transcription factor Pax6/Eyeless is a key regulator in this network. Eyeless acts cooperatively with Sine oculis and Eyes absent to regulate string, through a positive feed-forward loop. This loop is negatively modulated by the progenitor-specific transcription factor Homothorax/Meis1. This work shows that transcription factors that instruct cells to acquire an eye fate also control their proliferation regime, thus guaranteeing the coupling between proliferation and differentiation.
Vyšlo v časopise: Eye Selector Logic for a Coordinated Cell Cycle Exit. PLoS Genet 11(2): e32767. doi:10.1371/journal.pgen.1004981 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004981
1. Mann RS, Carroll SB (2002) Molecular mechanisms of selector gene function and evolution. Curr Opin Genet Dev 12 : 592–600. 12200165
2. Li CG, Eccles MR (2012) PAX Genes in Cancer; Friends or Foes? Front Genet 3 : 6. doi: 10.3389/fgene.2012.00006 22303411
3. Blake JA, Ziman MR (2014) Pax genes: regulators of lineage specification and progenitor cell maintenance. Development 141 : 737–751. doi: 10.1242/dev.091785 24496612
4. Dyer MA, Cepko CL (2001) Regulating proliferation during retinal development. Nat Rev Neurosci 2 : 333–342. 11331917
5. Bassett EA, Wallace VA (2012) Cell fate determination in the vertebrate retina. Trends Neurosci 35 : 565–573. doi: 10.1016/j.tins.2012.05.004 22704732
6. Sinn R, Wittbrodt J (2013) An eye on eye development. Mech Dev 130 : 347–358. doi: 10.1016/j.mod.2013.05.001 23684892
7. Glaser T, Jepeal L, Edwards JG, Young SR, Favor J, et al. (1994) PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet 7 : 463–471. 7951315
8. Sisodiya SM, Free SL, Williamson KA, Mitchell TN, Willis C, et al. (2001) PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans. Nat Genet 28 : 214–216. 11431688
9. Bai SW, Li B, Zhang H, Jonas JB, Zhao BW, et al. (2011) Pax6 regulates proliferation and apoptosis of human retinoblastoma cells. Invest Ophthalmol Vis Sci 52 : 4560–4570. doi: 10.1167/iovs.10-5487 21169528
10. Li L, Li B, Zhang H, Bai S, Wang Y, et al. (2011) Lentiviral vector-mediated PAX6 overexpression promotes growth and inhibits apoptosis of human retinoblastoma cells. Invest Ophthalmol Vis Sci 52 : 8393–8400. doi: 10.1167/iovs.11-8139 21948554
11. Wang J, Wang X, Wu G, Hou D, Hu Q (2013) MiR-365b-3p, down-regulated in retinoblastoma, regulates cell cycle progression and apoptosis of human retinoblastoma cells by targeting PAX6. FEBS Lett 587 : 1779–1786. doi: 10.1016/j.febslet.2013.04.029 23660406
12. Kumar JP (2011) My what big eyes you have: how the Drosophila retina grows. Dev Neurobiol 71 : 1133–1152. doi: 10.1002/dneu.20921 21604387
13. Treisman JE (2013) Retinal differentiation in Drosophila. Wiley Interdiscip Rev Dev Biol 2 : 545–557. doi: 10.1002/wdev.100 24014422
14. Amore G, Casares F (2010) Size matters: the contribution of cell proliferation to the progression of the specification Drosophila eye gene regulatory network. Dev Biol 344 : 569–577. doi: 10.1016/j.ydbio.2010.06.015 20599903
15. Cheyette BN, Green PJ, Martin K, Garren H, Hartenstein V, et al. (1994) The Drosophila sine oculis locus encodes a homeodomain-containing protein required for the development of the entire visual system. Neuron 12 : 977–996. 7910468
16. Czerny T, Halder G, Kloter U, Souabni A, Gehring WJ, et al. (1999) twin of eyeless, a second Pax-6 gene of Drosophila, acts upstream of eyeless in the control of eye development. Mol Cell 3 : 297–307. 10198632
17. Bessa J, Gebelein B, Pichaud F, Casares F, Mann RS (2002) Combinatorial control of Drosophila eye development by eyeless, homothorax, and teashirt. Genes Dev 16 : 2415–2427. 12231630
18. Peng HW, Slattery M, Mann RS (2009) Transcription factor choice in the Hippo signaling pathway: homothorax and yorkie regulation of the microRNA bantam in the progenitor domain of the Drosophila eye imaginal disc. Genes Dev 23 : 2307–2319. doi: 10.1101/gad.1820009 19762509
19. Lopes CS, Casares F (2010) hth maintains the pool of eye progenitors and its downregulation by Dpp and Hh couples retinal fate acquisition with cell cycle exit. Dev Biol 339 : 78–88. doi: 10.1016/j.ydbio.2009.12.020 20036228
20. Thomas BJ, Gunning DA, Cho J, Zipursky L (1994) Cell cycle progression in the developing Drosophila eye: roughex encodes a novel protein required for the establishment of G1. Cell 77 : 1003–1014. 8020091
21. Lehman DA, Patterson B, Johnston LA, Balzer T, Britton JS, et al. (1999) Cis-regulatory elements of the mitotic regulator, string/Cdc25. Development 126 : 1793–1803. 10101114
22. Mozer BA, Easwarachandran K (1999) Pattern formation in the absence of cell proliferation: tissue-specific regulation of cell cycle progression by string (stg) during Drosophila eye development. Dev Biol 213 : 54–69. 10452846
23. Jarman AP, Grell EH, Ackerman L, Jan LY, Jan YN (1994) Atonal is the proneural gene for Drosophila photoreceptors. Nature 369 : 398–400. 8196767
24. 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 : 4881–4889. 17108002
25. Zhou Q, Zhang T, Jemc JC, Chen Y, Chen R, et al. (2014) Onset of atonal expression in Drosophila retinal progenitors involves redundant and synergistic contributions of Ey/Pax6 and So binding sites within two distant enhancers. Dev Biol 386 : 152–164. doi: 10.1016/j.ydbio.2013.11.012 24247006
26. Tanaka-Matakatsu M, Du W (2008) Direct control of the proneural gene atonal by retinal determination factors during Drosophila eye development. Dev Biol 313 : 787–801. 18083159
27. Peter IS, Davidson EH (2011) Evolution of gene regulatory networks controlling body plan development. Cell 144 : 970–985. doi: 10.1016/j.cell.2011.02.017 21414487
28. Hauck B, Gehring WJ, Walldorf U (1999) Functional analysis of an eye specific enhancer of the eyeless gene in Drosophila. Proc Natl Acad Sci U S A 96 : 564–569. 9892673
29. Atkins M, Jiang Y, Sansores-Garcia L, Jusiak B, Halder G, et al. (2013) Dynamic rewiring of the Drosophila retinal determination network switches its function from selector to differentiation. PLoS Genet 9: e1003731. doi: 10.1371/journal.pgen.1003731 24009524
30. Niimi T, Seimiya M, Kloter U, Flister S, Gehring WJ (1999) Direct regulatory interaction of the eyeless protein with an eye-specific enhancer in the sine oculis gene during eye induction in Drosophila. Development 126 : 2253–2260. 10207149
31. Punzo C, Seimiya M, Flister S, Gehring WJ, Plaza S (2002) Differential interactions of eyeless and twin of eyeless with the sine oculis enhancer. Development 129 : 625–634. 11830564
32. Bui QT, Zimmerman JE, Liu H, Gray-Board GL, Bonini NM (2000) Functional analysis of an eye enhancer of the Drosophila eyes absent gene: differential regulation by eye specification genes. Dev Biol 221 : 355–364. 10790331
33. Pappu KS, Ostrin EJ, Middlebrooks BW, Sili BT, Chen R, et al. (2005) Dual regulation and redundant function of two eye-specific enhancers of the Drosophila retinal determination gene dachshund. Development 132 : 2895–2905. 15930118
34. Ostrin EJ, Li Y, Hoffman K, Liu J, Wang K, et al. (2006) Genome-wide identification of direct targets of the Drosophila retinal determination protein Eyeless. Genome Res 16 : 466–476. 16533912
35. Sun Y, Jan LY, Jan YN (1998) Transcriptional regulation of atonal during development of the Drosophila peripheral nervous system. Development 125 : 3731–3740. 9716538
36. Escudero LM, Freeman M (2007) Mechanism of G1 arrest in the Drosophila eye imaginal disc. BMC Dev Biol 7 : 13. 17335573
37. Narlikar L, Ovcharenko I (2009) Identifying regulatory elements in eukaryotic genomes. Brief Funct Genomic Proteomic 8 : 215–230. doi: 10.1093/bfgp/elp014 19498043
38. Bushey AM, Ramos E, Corces VG (2009) Three subclasses of a Drosophila insulator show distinct and cell type-specific genomic distributions. Genes Dev 23 : 1338–1350. doi: 10.1101/gad.1798209 19443682
39. Gurudatta BV, Corces VG (2009) Chromatin insulators: lessons from the fly. Brief Funct Genomic Proteomic 8 : 276–282. doi: 10.1093/bfgp/elp032 19752045
40. Negre N, Brown CD, Ma L, Bristow CA, Miller SW, et al. (2011) A cis-regulatory map of the Drosophila genome. Nature 471 : 527–531. doi: 10.1038/nature09990 21430782
41. Wallace JA, Felsenfeld G (2007) We gather together: insulators and genome organization. Curr Opin Genet Dev 17 : 400–407. 17913488
42. Baonza A, Murawsky CM, Travers AA, Freeman M (2002) Pointed and Tramtrack69 establish an EGFR-dependent transcriptional switch to regulate mitosis. Nat Cell Biol 4 : 976–980. 12447387
43. Sandelin A, Alkema W, Engstrom P, Wasserman WW, Lenhard B (2004) JASPAR: an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res 32: D91–94. 14681366
44. Wingender E (2008) The TRANSFAC project as an example of framework technology that supports the analysis of genomic regulation. Brief Bioinform 9 : 326–332. doi: 10.1093/bib/bbn016 18436575
45. Bailey TL, Elkan C (1994) Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Proc Int Conf Intell Syst Mol Biol 2 : 28–36. 7584402
46. Blanco E, Corominas M (2012) CBS: an open platform that integrates predictive methods and epigenetics information to characterize conserved regulatory features in multiple Drosophila genomes. BMC Genomics 13 : 688. doi: 10.1186/1471-2164-13-688 23228284
47. Jacobsson L, Kronhamn J, Rasmuson-Lestander A (2009) The Drosophila Pax6 paralogs have different functions in head development but can partially substitute for each other. Mol Genet Genomics 282 : 217–231. doi: 10.1007/s00438-009-0458-2 19484263
48. Pignoni F, Hu B, Zavitz KH, Xiao J, Garrity PA, et al. (1997) The eye-specification proteins So and Eya form a complex and regulate multiple steps in Drosophila eye development. Cell 91 : 881–891. 9428512
49. Kumar JP (2009) The molecular circuitry governing retinal determination. Biochim Biophys Acta 1789 : 306–314. doi: 10.1016/j.bbagrm.2008.10.001 19013263
50. Jemc J, Rebay I (2007) Identification of transcriptional targets of the dual-function transcription factor/phosphatase eyes absent. Dev Biol 310 : 416–429. 17714699
51. Lee T, Luo L (1999) Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22 : 451–461. 10197526
52. Chen R, Amoui M, Zhang Z, Mardon G (1997) Dachshund and eyes absent proteins form a complex and function synergistically to induce ectopic eye development in Drosophila. Cell 91 : 893–903. 9428513
53. Rieckhof GE, Casares F, Ryoo HD, Abu-Shaar M, Mann RS (1997) Nuclear translocation of extradenticle requires homothorax, which encodes an extradenticle-related homeodomain protein. Cell 91 : 171–183. 9346235
54. Pichaud F, Casares F (2000) homothorax and iroquois-C genes are required for the establishment of territories within the developing eye disc. Mech Dev 96 : 15–25. 10940621
55. Morata G, Ripoll P (1975) Minutes: mutants of drosophila autonomously affecting cell division rate. Dev Biol 42 : 211–221. 1116643
56. Halder G, Callaerts P, Gehring WJ (1995) Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science 267 : 1788–1792. 7892602
57. Salzer CL, Kumar JP (2010) Identification of retinal transformation hot spots in developing Drosophila epithelia. PLoS One 5: e8510. doi: 10.1371/journal.pone.0008510 20062803
58. Bonini NM, Bui QT, Gray-Board GL, Warrick JM (1997) The Drosophila eyes absent gene directs ectopic eye formation in a pathway conserved between flies and vertebrates. Development 124 : 4819–4826. 9428418
59. Tadjuidje E, Hegde RS (2013) The Eyes Absent proteins in development and disease. Cell Mol Life Sci 70 : 1897–1913. doi: 10.1007/s00018-012-1144-9 22971774
60. Boutros R, Lobjois V, Ducommun B (2007) CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer 7 : 495–507. 17568790
61. Quiring R, Walldorf U, Kloter U, Gehring WJ (1994) Homology of the eyeless gene of Drosophila to the Small eye gene in mice and Aniridia in humans. Science 265 : 785–789. 7914031
62. Clements J, Hens K, Merugu S, Dichtl B, de Couet HG, et al. (2009) Mutational analysis of the eyeless gene and phenotypic rescue reveal that an intact Eyeless protein is necessary for normal eye and brain development in Drosophila. Dev Biol 334 : 503–512. doi: 10.1016/j.ydbio.2009.08.003 19666017
63. Xie Q, Cvekl A (2011) The orchestration of mammalian tissue morphogenesis through a series of coherent feed-forward loops. J Biol Chem 286 : 43259–43271. doi: 10.1074/jbc.M111.264580 21998302
64. Kurant E, Pai CY, Sharf R, Halachmi N, Sun YH, et al. (1998) Dorsotonals/homothorax, the Drosophila homologue of meis1, interacts with extradenticle in patterning of the embryonic PNS. Development 125 : 1037–1048. 9463350
65. Mardon G, Solomon NM, Rubin GM (1994) dachshund encodes a nuclear protein required for normal eye and leg development in Drosophila. Development 120 : 3473–3486. 7821215
66. Bonini NM, Leiserson WM, Benzer S (1993) The eyes absent gene: genetic control of cell survival and differentiation in the developing Drosophila eye. Cell 72 : 379–395. 8431945
67. Hazelett DJ, Bourouis M, Walldorf U, Treisman JE (1998) decapentaplegic and wingless are regulated by eyes absent and eyegone and interact to direct the pattern of retinal differentiation in the eye disc. Development 125 : 3741–3751. 9716539
68. Struhl G, Basler K (1993) Organizing activity of wingless protein in Drosophila. Cell 72 : 527–540. 8440019
69. 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
70. 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
71. Royo JL, Maeso I, Irimia M, Gao F, Peter IS, et al. (2011) Transphyletic conservation of developmental regulatory state in animal evolution. Proc Natl Acad Sci U S A 108 : 14186–14191. doi: 10.1073/pnas.1109037108 21844364
72. Pfeiffer BD, Jenett A, Hammonds AS, Ngo TT, Misra S, et al. (2008) Tools for neuroanatomy and neurogenetics in Drosophila. Proc Natl Acad Sci U S A 105 : 9715–9720. doi: 10.1073/pnas.0803697105 18621688
73. Lai R, Bekessy A, Chen CC, Walsh T, Barnard R (2003) Megaprimer mutagenesis using very long primers. Biotechniques 34 : 52–54, 56. 12545538
74. Casares F, Mann RS (1998) Control of antennal versus leg development in Drosophila. Nature 392 : 723–726. 9565034
75. Jacobs H, Richter D, Venkatesh T, Lehner C (2002) Completion of mitosis requires neither fzr/rap nor fzr2, a male germline-specific Drosophila Cdh1 homolog. Curr Biol 12 : 1435–1441. 12194827
76. 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
77. Sandmann T, Jakobsen JS, Furlong EE (2006) ChIP-on-chip protocol for genome-wide analysis of transcription factor binding in Drosophila melanogaster embryos. Nat Protoc 1 : 2839–2855. 17406543
78. Pauli T, Seimiya M, Blanco J, Gehring WJ (2005) Identification of functional sine oculis motifs in the autoregulatory element of its own gene, in the eyeless enhancer and in the signalling gene hedgehog. Development 132 : 2771–2782. 15901665
79. Firth LC, Baker NE (2009) Retinal determination genes as targets and possible effectors of extracellular signals. Dev Biol 327 : 366–375. doi: 10.1016/j.ydbio.2008.12.021 19135045
80. Anderson AM, Weasner BM, Weasner BP, Kumar JP (2012) Dual transcriptional activities of SIX proteins define their roles in normal and ectopic eye development. Development 139 : 991–1000. doi: 10.1242/dev.077255 22318629
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