A context-dependent bifurcation in the Pointed transcriptional effector network contributes specificity and robustness to retinal cell fate acquisition

English version

Autoři: Chudong Wu ^aff001; Jean-François Boisclair Lachance ^aff002; Michael Z. Ludwig ^aff003; Ilaria Rebay ^aff001
Působiště autorů: Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, Illinois, United States of America ^aff001; Department of Human Genetics, McGill University, Montreal, Quebec, Canada ^aff002; Department of Ecology and Evolution, University of Chicago, Chicago, Illinois, United States of America ^aff003; Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, United States of America ^aff004
Vyšlo v časopise: A context-dependent bifurcation in the Pointed transcriptional effector network contributes specificity and robustness to retinal cell fate acquisition. PLoS Genet 16(11): e1009216. doi:10.1371/journal.pgen.1009216
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009216

Souhrn

Spatiotemporally precise and robust cell fate transitions, which depend on specific signaling cues, are fundamental to the development of appropriately patterned tissues. The fidelity and precision with which photoreceptor fates are recruited in the Drosophila eye exemplifies these principles. The fly eye consists of a highly ordered array of ~750 ommatidia, each of which contains eight distinct photoreceptors, R1-R8, specified sequentially in a precise spatial pattern. Recruitment of R1-R7 fates requires reiterative receptor tyrosine kinase / mitogen activated protein kinase (MAPK) signaling mediated by the transcriptional effector Pointed (Pnt). However the overall signaling levels experienced by R2-R5 cells are distinct from those experienced by R1, R6 and R7. A relay mechanism between two Pnt isoforms initiated by MAPK activation directs the universal transcriptional response. Here we ask how the generic Pnt response is tailored to these two rounds of photoreceptor fate transitions. We find that during R2-R5 specification PntP2 is coexpressed with a closely related but previously uncharacterized isoform, PntP3. Using CRISPR/Cas9-generated isoform specific null alleles we show that under otherwise wild type conditions, R2-R5 fate specification is robust to loss of either PntP2 or PntP3, and that the two activate pntP1 redundantly; however under conditions of reduced MAPK activity, both are required. Mechanistically, our data suggest that intrinsic activity differences between PntP2 and PntP3, combined with positive and unexpected negative transcriptional auto- and cross-regulation, buffer first-round fates against conditions of compromised RTK signaling. In contrast, in a mechanism that may be adaptive to the stronger signaling environment used to specify R1, R6 and R7 fates, the Pnt network resets to a simpler topology in which PntP2 uniquely activates pntP1 and auto-activates its own transcription. We propose that differences in expression patterns, transcriptional activities and regulatory interactions between Pnt isoforms together facilitate context-appropriate cell fate specification in different signaling environments.

Klíčová slova:

Cloning – DNA transcription – Drosophila melanogaster – Eyes – Homozygosity – MAPK signaling cascades – Photoreceptors – Transcriptional control

Zdroje

1. Flores GV, Duan H, Yan H, Nagaraj R, Fu W, Zou Y, et al. Combinatorial signaling in the specification of unique cell fates. Cell. 2000;103:75–85. doi: 10.1016/s0092-8674(00)00106-9 11051549

2. Halfon MS, Carmena A, Gisselbrecht S, Sackerson CM, Jiménez F, Baylies MK, et al. Ras pathway specificity is determined by the integration of multiple signal-activated and tissue-restricted transcription factors. Cell. 2000;103:63–74. doi: 10.1016/s0092-8674(00)00105-7 11051548

3. Voas MG, Rebay I. Signal Integration during Development: Insights from the Drosophila Eye. Dev Dyn. 2004;229:162–175. doi: 10.1002/dvdy.10449 14699588

4. Wolpert L. Positional information and the spatial pattern of cellular differentiation. J Theor Biol. 1969;25:1–47. doi: 10.1016/s0022-5193(69)80016-0 4390734

5. Guillemot F. Spatial and temporal specification of neural fates by transcription factor codes. Development. 2007;134:3771–3780. doi: 10.1242/dev.006379 17898002

6. Cagan R. Principles of Drosophila Eye Differentiation. 1st ed. Current Topics in Developmental Biology. Elsevier Inc.; 2009. doi: 10.1016/S0070-2153(09)89005-4 19737644

7. Félix MA, Barkoulas M. Robustness and flexibility in nematode vulva development. Trends Genet. 2012;28:185–195. doi: 10.1016/j.tig.2012.01.002 22325232

8. Liu K, Xu K, Song Y. Faster, higher, stronger: Timely and robust cell fate/identity commitment in stem cell lineages. Open Biol. 2019;9. doi: 10.1098/rsob.180243 30958098

9. Wolff T, Ready DF. The beginning of pattern formation in the Drosophila compound eye: the morphogenetic furrow and the second mitotic wave. Development. 1991;113:841–50. 1726564

10. Ready F, Hanson E. Developmen of the Drosophila Retina, a Neurocrystalline. Dev Biol. 1976;240.

11. Tomlinson A, Ready DF. Neuronal differentiation in the Drosophila ommatidium. Dev Biol. 1987;120:366–376. doi: 10.1016/0012-1606(87)90239-9 17985475

12. Freeman M. Reiterative Use of the EGF Receptor Trigger Differentiation of All Cell Types in the Drosophila Eye. Cell. 1996;87:651–660. doi: 10.1016/s0092-8674(00)81385-9 8929534

13. Scholz H, Deatrick J, Klaes A, Klambt C. Genetic dissection of pointed, a Drosophila gene encoding two ETS-related proteins. Genetics. 1993;135:455–468. 8244007

14. Domingos PM, Mlodzik M, Mendes CS, Brown S, Steller H, Mollereau B. Spalt transcription factors are required for R3/R4 specification and establishment of planar cell polarity in the Drosophila eye. Development. 2004;131:5695–5702. doi: 10.1242/dev.01443 15509769

15. Weber U, Pataki C, Mihaly J, Mlodzik M. Combinatorial signaling by the Frizzled/PCP and Egfr pathways during planar cell polarity establishment in the Drosophila eye. Dev Biol. 2008;316:110–123. doi: 10.1016/j.ydbio.2008.01.016 18291359

16. Xu C, Kauffmann RC, Zhang J, Kladny S, Carthew RW. Overlapping Activators and Repressors Delimit Transcriptional Response to Receptor Tyrosine Kinase Signals in the Drosophila Eye. Cell. 2000;103:87–97. doi: 10.1016/s0092-8674(00)00107-0 11051550

17. Hayashi T, Xu C, Carthew RW. Cell-type-specific transcription of prospero is controlled by combinatorial signaling in the Drosophila eye. Development. 2008;135:2787–2796. doi: 10.1242/dev.006189 18635611

18. Basler K, Hafen E. Sevenless and Drosophila eye development: a tyrosine kinase controls cell fate. Trends Genet. 1988;4. doi: 10.1016/0168-9525(88)90044-3 3076295

19. Reinke R, Zipursky SL. Cell-cell interaction in the drosophila retina: The bride of sevenless gene is required in photoreceptor cell R8 for R7 cell development. Cell. 1988;55:321–330. doi: 10.1016/0092-8674(88)90055-4 3167983

20. Tomlinson A, Mavromatakis YE, Struhl G. Three distinct roles for Notch in Drosophila R7 photoreceptor specification. PLoS Biol. 2011;9. doi: 10.1371/journal.pbio.1001132 21886484

21. Tomlinson A, Mavromatakis YE, Arias R. The role of Sevenless in Drosophila R7 photoreceptor specification. Dev Biol. 2019;454:181–189. doi: 10.1016/j.ydbio.2019.06.007 31207209

22. Klambt C. The Drosophila gene pointed encodes two ETS-like proteins which are involved in the development of the midline glial cells. Development. 1993;117:163–176. 8223245

23. Brunner D, Dücker K, Oellers N, Hafen E, Scholz H, Klämbt C. The ETS domain protein pointed-P2 is a target of MAP kinase in the sevenless signal transduction pathway. Nature. 1994. pp. 386–389. doi: 10.1038/370386a0 8047146

24. O’Neill EMD, Tjian R, Rubin GM. The Activities of Two Ets-Related Transcription Factors Required for Drosophila Eye Development Are Modulated by the Ras / MAPK Pathway. Cell. 1994;78:137–147. doi: 10.1016/0092-8674(94)90580-0 8033205

25. Shwartz A, Yogev S, Schejter ED, Shilo B. Sequential activation of ETS proteins provides a sustained transcriptional response to EGFR signaling. Development. 2013;140:2746–2754. doi: 10.1242/dev.093138 23757412

26. Qiao F, Harada B, Song H, Whitelegge J, Courey AJ, Bowie JU. Mae inhibits Pointed-P2 transcriptional activity by blocking its MAPK docking site. EMBO J. 2006;25:70–79. doi: 10.1038/sj.emboj.7600924 16362034

27. Tootle TL, Lee PS, Rebay I. CRM1-mediated nuclear export and regulated activity of the receptor tyrosine kinase antagonist YAN require specific interactions with MAE. Development. 2003;130:845–857. doi: 10.1242/dev.00312 12538513

28. Wasylyk C, Bradford a P, Gutierrez-Hartmann a, Wasylyk B. Conserved mechanisms of Ras regulation of evolutionary related transcription factors, Ets1 and Pointed P2. Oncogene. 1997;14:899–913. doi: 10.1038/sj.onc.1200914 9050989

29. Brunner D, Oellers N, Szabad J, Biggs WH, Zipursky SL, Hafen E. A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways. Cell. 1994;76:875–888. doi: 10.1016/0092-8674(94)90362-x 8124723

30. Celniker SE, Dillon LAL, Gerstein MB, Gunsalus KC, Henikoff S, Karpen GH, et al. Unlocking the secrets of the genome. Nature. 2009;459:927–930. doi: 10.1038/459927a 19536255

31. Leader DP, Krause SA, Pandit A, Davies SA, Dow JAT. FlyAtlas 2: A new version of the Drosophila melanogaster expression atlas with RNA-Seq, miRNA-Seq and sex-specific data. Nucleic Acids Res. 2018;46:D809–D815. doi: 10.1093/nar/gkx976 29069479

32. Rubin GM, Hong L, Brokstein P, Evans-Holm M, Frise E, Stapleton M, et al. A Drosophila Complementary DNA Resource. Science (80-). 2000;287:2222 LP– 2224. doi: 10.1126/science.287.5461.2222 10731138

33. Yang L, Baker NE. Cell cycle withdrawal, progression, and cell survival regulation by EGFR and its effectors in the differentiating Drosophila eye. Developmental Cell. 2003. pp. 359–369. doi: 10.1016/S1534-5807(03)00059-5

34. Boisclair Lachance J-F, Peláez N, Cassidy JJ, Webber JL, Rebay I, Carthew RW. A comparative study of Pointed and Yan expression reveals new complexity to the transcriptional networks downstream of receptor tyrosine kinase signaling. Dev Biol. 2013/11/14. 2014;385:263–278. doi: 10.1016/j.ydbio.2013.11.002 24240101

35. Wolff T, Ready DF. Pattern formation in the Drosophila retina. Cold Spring Harb Lab Press. 1993;2:1277–1325. Available: http://www.sdbonline.org/sites/fly/vdevlhom/movie.htm

36. Peláez N, Gavalda-miralles A, Wang B, Navarro HT, Rebay I, Dinner AR, et al. Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation. 2015.

37. Morimoto AM, Jordan KC, Tietze K, Britton JS, O’Neill EM, Ruohola-Baker H. Pointed, an ETS domain transcription factor, negatively regulates the EGF receptor pathway in Drosophila oogenesis. Development. 1996;122:3745–3754. 9012496

38. Paul L, Wang S, Manivannan SN, Bonanno L, Lewis S, Austin CL, et al. Dpp-induced Egfr signaling triggers postembryonic wing development in Drosophila. Proc Natl Acad Sci. 2013;110:5058–63. doi: 10.1073/pnas.1217538110 23479629

39. Rebay I, Rubin GM. Yan functions as a general inhibitor of differentiation and is negatively regulated by activation of the Ras1/MAPK pathway. Cell. 1995;81:857–866. doi: 10.1016/0092-8674(95)90006-3 7781063

40. Rebay I, Chen F, Hsiao F, Kolodziej P a, Kuang BH, Laverty T, et al. A Genetic Screen for Novel Components of the Ras/Mitogen-Activated Protein Kinase Signaling Pathway That Interact With the. Genetics. 2000;154:695–712. 10655223

41. Tomlinson A, Bowtell DDL, Hafen E, Rubin GM. Localization of the sevenless protein, a putative receptor for positional information, in the eye imaginal disc of Drosophila. Cell. 1987;51:143–150. doi: 10.1016/0092-8674(87)90019-5 3115593

42. Basler K, Siegrist P, Hafen E. The spatial and temporal expression pattern of sevenless is exclusively controlled by gene-internal elements. EMBO J. 1989;8:2381–2386. doi: 10.1002/j.1460-2075.1989.tb08367.x 2792089

43. Karim FD, Chang HC, Therrien M, Wassarman DA, Laverty T, Rubin GM. A screen for genes that function downstream of Ras1 during Drosophila eye development. Genetics. 1996;143:315–329. 8722784

44. Prober DA, Edgar BA. Ras1 promotes cellular growth in the Drosophila wing. Cell. 2000;100:435–446. doi: 10.1016/s0092-8674(00)80679-0 10693760

45. Kurada P, White K. Ras Promotes Cell Survival in Drosophila by Downregulating hid Expression. Cell. 1998;95:319–329. doi: 10.1016/s0092-8674(00)81764-x 9814703

46. Rohrbaugh M, Ramos E, Nguyen D, Price M, Wen Y, Lai ZC. Notch activation of yan expression is antagonized by RTK/pointed signaling in the Drosophila eye. Curr Biol. 2002;12:576–581. doi: 10.1016/s0960-9822(02)00743-1 11937027

47. Zhu S, Barshow S, Wildonger J, Jan LY, Jan Y-N. Ets transcription factor Pointed promotes the generation of intermediate neural progenitors in <em>Drosophila</em> larval brains. Proc Natl Acad Sci. 2011;108:20615 LP– 20620. doi: 10.1073/pnas.1118595109 22143802

48. Webber JL, Zhang J, Massey A, Sanchez-Luege N, Rebay I. Collaborative repressive action of the antagonistic ETS transcription factors Pointed and Yan fine-tunes gene expression to confer robustness in Drosophila. Dev. 2018;145. doi: 10.1242/dev.165985 29848501

49. Singh A, Hespanha JP. Optimal feedback strength for noise suppression in autoregulatory gene networks. Biophys J. 2009;96:4013–4023. doi: 10.1016/j.bpj.2009.02.064 19450473

50. Voliotis M, Bowsher CG. The magnitude and colour of noise in genetic negative feedback systems. Nucleic Acids Res. 2012;40:7084–7095. doi: 10.1093/nar/gks385 22581772

51. Chang HH, Hemberg M, Barahona M, Ingber DE, Huang S. Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature. 2008;453:544–547. doi: 10.1038/nature06965 18497826

52. Stark WS, Walker JA, Harris WA. Genetic dissection of the photoreceptor system in the compound eye of Drosophila melanogaster. J Physiol. 1976;256:415–439. doi: 10.1113/jphysiol.1976.sp011331 16992509

53. Basler K, Hafen E. Dynamics of Drosophila eye development and temporal requirements of sevenless expression. Development. 1989;107:723–731. 2632232

54. Fortini ME, Simon MA, Rubin GM. Signalling by the sevenless protein tyrosine kinase is mimicked by Has1 activation. 1992;355:559–561.

55. Yang X, Coulombe-Huntington J, Kang S, Sheynkman GM, Hao T, Richardson A, et al. Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell. 2016;164:805–817. doi: 10.1016/j.cell.2016.01.029 26871637

56. Yang L, Baker NE. Role of the EGFR/Ras/Raf pathway in specification of photoreceptor cells in the Drosophila retina. Development. 2001;128:1183–1191. Available: http://www.ncbi.nlm.nih.gov/pubmed/11245584 11245584

57. Frankfort BJ, Mardon G. R8 development in the Drosophila eye: A paradigm for neural selection and differentiation. Development. 2002;129:1295–1306. 11880339

58. Kumar JP, Tio M, Hsiung F, Akopyan S, Gabay L, Seger R, et al. Dissecting the roles of the Drosophila EGF receptor in eye development and MAP kinase activation. Development. 1998;125:3875–3885. 9729495

59. Domínguez M, Wasserman JD, Freeman M. Multiple functions of the EGF receptor in Drosophila eye development. Curr Biol. 1998;8:1039–1048. doi: 10.1016/s0960-9822(98)70441-5 9768358

60. Watson DK, Mcwilliams MJ, Lapis P, Lautenberger JA, Schweinfest CW, Papas TS. Mammalian ets-1 and ets-2 genes encode highly conserved proteins. 1988;85:7862–7866. doi: 10.1073/pnas.85.21.7862 2847145

61. Albagli O, Soudant N, Ferreira E, Dhordain P, Dewitte F, Bégue A, et al. A model for gene evolution of the ets-1/ets-2 transcription factors based on structural and functional homologies. Oncogene. 1994;9 11:3259–3271.

62. Mavromatakis YE, Tomlinson A. Switching cell fates in the developing Drosophila eye. Development. 2013;140:4353–61. doi: 10.1242/dev.096925 24067351

63. Bischof J, Maeda RK, Hediger M, Karch F, Basler K. An optimized transgenesis system for <em>Drosophila</em> using germ-line-specific φC31 integrases. Proc Natl Acad Sci. 2007;104:3312 LP– 3317 doi: 10.1073/pnas.0611511104

64. Venken KJT, Carlson JW, Schulze KL, Pan H, He Y, Spokony R, et al. Versatile P[acman] BAC libraries for transgenesis studies in Drosophila melanogaster. Nat Methods. 2009;6:431–434. doi: 10.1038/nmeth.1331 19465919

65. Li Xin, Cassidy Justin J., Reinke Catherine A., Fischboeck Stephen and R WC. A microRNA Imparts Robustness Against Environmental Fluctuation During Development. Cell. 2009;23:1–7. doi: 10.1016/j.cell.2009.01.058 19379693

66. Ponton F, Chapuis MP, Pernice M, Sword GA, Simpson SJ. Evaluation of potential reference genes for reverse transcription-qPCR studies of physiological responses in Drosophila melanogaster. J Insect Physiol. 2011;57:840–850. doi: 10.1016/j.jinsphys.2011.03.014 21435341

67. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods. 2001;25:402–408. doi: 10.1006/meth.2001.1262 11846609

68. Gratz SJ, Cummings AM, Nguyen JN, Hamm DC, Donohue LK, Harrison MM, et al. Genome engineering of Drosophila with the CRISPR RNA-guided Cas9 nuclease. Genetics. 2013;194:1029–1035. doi: 10.1534/genetics.113.152710 23709638

69. Ren X, Sun J, Housden BE, Hu Y, Roesel C, Lin S, et al. Optimized gene editing technology for Drosophila melanogaster using germ line-specific Cas9. Proc Natl Acad Sci U S A. 2013;110:19012–19017. doi: 10.1073/pnas.1318481110 24191015

70. Peláez N, Gavalda-Miralles A, Wang B, Navarro HT, Gudjonson H, Rebay I, et al. Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation. Elife. 2015; 4. doi: 10.7554/eLife.08924 26583752

Článek A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population

Článek Mms19 promotes spindle microtubule assembly in Drosophila neural stem cells

Článek Mosquito genomes are frequently invaded by transposable elements through horizontal transfer

Článek Genotype imputation using the Positional Burrows Wheeler Transform

Článek Formal commentary

Článek The DNA damage response is required for oocyte cyst breakdown and follicle formation in mice

Článek Loss of hepatocyte cell division leads to liver inflammation and fibrosis

Článek A genetic variant controls interferon-β gene expression in human myeloid cells by preventing C/EBP-β binding on a conserved enhancer

Článek Identity-by-descent with uncertainty characterises connectivity of Plasmodium falciparum populations on the Colombian-Pacific coast

Článek A proteomic survey of microtubule-associated proteins in a R402H TUBA1A mutant mouse

Článek Inferring causal direction between two traits in the presence of horizontal pleiotropy with GWAS summary data

Článek A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease