Origins of Context-Dependent Gene Repression by Capicua

English version České info

Understanding the evolution of developmental regulatory mechanisms is a central challenge of biology. Here we uncover a newly evolved mechanism of transcriptional repression by Capicua (Cic), a conserved sensor of Receptor Tyrosine Kinase (RTK) signaling. In Drosophila, Cic patterns the central regions of the embryo by repressing genes induced by Torso RTK signaling at the poles. We show that Cic performs this function by recruiting the Groucho (Gro) corepressor and that this mechanism is an evolutionary innovation of dipteran insects. Indeed, we find that recruitment of Gro depends on a short motif of Cic (N2) specific to dipterans. Strikingly, moreover, the form of Cic that existed before the origin of dipterans is completely inactive in fly embryos, whereas the equivalent form carrying N2 displays significant function. This suggests that evolution of the N2 motif caused a fundamental change in Cic repressor activity, which we propose has enabled the complex roles of Cic, Gro and Torso signaling in fly embryonic patterning. In contrast, Cic functions independently of Gro in other Drosophila tissues and probably also in mammals, where Cic lacks the N2 sequence. Thus, our results illustrate the structural and evolutionary origins of essential functional variations within a highly conserved family of developmental regulators.

Vyšlo v časopise: Origins of Context-Dependent Gene Repression by Capicua. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004902
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004902

Souhrn

Zdroje

1. LemmonMA, SchlessingerJ (2010) Cell signaling by receptor tyrosine kinases. Cell 141: 1117–1134.

2. JiménezG, ShvartsmanSY, ParoushZ (2012) The Capicua repressor - a general sensor of RTK signaling in development and disease. J Cell Sci 125: 1383–1391.

3. JiménezG, GuichetA, EphrussiA, CasanovaJ (2000) Relief of gene repression by Torso RTK signaling: role of capicua in Drosophila terminal and dorsoventral patterning. Genes Dev 14: 224–231.

4. GoffDJ, NilsonLA, MorisatoD (2001) Establishment of dorsal-ventral polarity of the Drosophila egg requires capicua action in ovarian follicle cells. Development 128: 4553–4562.

5. RochF, JiménezG, CasanovaJ (2002) EGFR signalling inhibits Capicua-dependent repression during specification of Drosophila wing veins. Development 129: 993–1002.

6. AtkeyMR, LachanceJF, WalczakM, RebelloT, NilsonLA (2006) Capicua regulates follicle cell fate in the Drosophila ovary through repression of mirror. Development 133: 2115–2123.

7. AstigarragaS, GrossmanR, Diaz-DelfinJ, CaellesC, ParoushZ, et al. (2007) A MAPK docking site is critical for downregulation of Capicua by Torso and EGFR RTK signaling. EMBO J 26: 668–677.

8. TsengAS, TaponN, KandaH, CigizogluS, EdelmannL, et al. (2007) Capicua regulates cell proliferation downstream of the receptor tyrosine kinase/Ras signaling pathway. Curr Biol 17: 728–733.

9. LöhrU, ChungHR, BellerM, JackleH (2009) Antagonistic action of Bicoid and the repressor Capicua determines the spatial limits of Drosophila head gene expression domains. Proc Natl Acad Sci U S A 106: 21695–21700.

10. AjuriaL, NievaC, WinklerC, KuoD, SamperN, et al. (2011) Capicua DNA-binding sites are general response elements for RTK signaling in Drosophila. Development 138: 915–924.

11. AndreuMJ, González-PérezE, AjuriaL, SamperN, Gonzalez-CrespoS, et al. (2012) Mirror represses pipe expression in follicle cells to initiate dorsoventral axis formation in Drosophila. Development 139: 1110–1114.

12. AndreuMJ, AjuriaL, SamperN, González-PérezE, CampuzanoS, et al. (2012) EGFR-dependent downregulation of Capicua and the establishment of Drosophila dorsoventral polarity. Fly 6: 234–239.

13. GrimmO, Sanchez ZiniV, KimY, CasanovaJ, ShvartsmanSY, et al. (2012) Torso RTK controls Capicua degradation by changing its subcellular localization. Development 139: 3962–3968.

14. LamYC, BowmanAB, Jafar-NejadP, LimJ, RichmanR, et al. (2006) ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 127: 1335–1347.

15. FryerJD, YuP, KangH, Mandel-BrehmC, CarterAN, et al. (2011) Exercise and genetic rescue of SCA1 via the transcriptional repressor Capicua. Science 334: 690–693.

16. BettegowdaC, AgrawalN, JiaoY, SausenM, WoodLD, et al. (2011) Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 333: 1453–1455.

17. LeeY, FryerJD, KangH, Crespo-BarretoJ, BowmanAB, et al. (2011) ATXN1 protein family and CIC regulate extracellular matrix remodeling and lung alveolarization. Dev Cell 21: 746–757.

18. Kawamura-SaitoM, YamazakiY, KanekoK, KawaguchiN, KandaH, et al. (2006) Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35; q13) translocation. Hum Mol Genet 15: 2125–2137.

19. DissanayakeK, TothR, BlakeyJ, OlssonO, CampbellDG, et al. (2011) ERK/p90(RSK)/14-3-3 signalling has an impact on expression of PEA3 Ets transcription factors via the transcriptional repressor capicua. Biochem J 433: 515–525.

20. LimJ, Crespo-BarretoJ, Jafar-NejadP, BowmanAB, RichmanR, et al. (2008) Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452: 713–718.

21. KimE, LuH, ZoghbiHY, SongJ (2013) Structural basis of protein complex formation and reconfiguration by polyglutamine disease protein Ataxin-1 and Capicua. Genes Dev 27: 590–595.

22. JenningsBH, Ish-HorowiczD (2008) The Groucho/TLE/Grg family of transcriptional co-repressors. Genome Biol 9: 205.

23. Turki-JudehW, CoureyAJ (2012) Groucho: a corepressor with instructive roles in development. Curr Top Dev Biol 98: 65–96.

24. MannervikM (2014) Control of Drosophila embryo patterning by transcriptional co-regulators. Exp Cell Res 321: 47–57.

25. ParoushZ, WainwrightSM, Ish-HorowiczD (1997) Torso signalling regulates terminal patterning in Drosophila by antagonising Groucho-mediated repression. Development 124: 3827–3834.

26. ParkhurstSM, BoppD, Ish-HorowiczD (1990) X:A ratio, the primary sex-determining signal in Drosophila, is transduced by helix-loop-helis proteins. Cell 63: 1179–1191.

27. JiménezG, ParoushZ, Ish-HorowiczD (1997) Groucho acts as corepressor for a subset of negative regulators, including Hairy and Engrailed. Genes Dev 11: 3072–3082.

28. JenningsBH, PicklesLM, PearlLH, Ish-HorowiczD (2006) Molecular recognition of transcriptional repressor motifs by the WD domain of the Groucho/TLE corepressor. Mol Cell 22: 645–655.

29. HittingerCT, CarrollSB (2008) Evolution of an insect-specific Groucho-interaction motif in the Engrailed selector protein. Evol Dev 10: 537–545.

30. CarrollSB (2008) Evo-devo and an expanding evolutionary synthesis: a genetic theory of morphological evolution. Cell 134: 25–36.

31. AronsonBD, FisherAL, BlechmanK, CaudyM, GergenJP (1997) Groucho-dependent and -independent repression activities of Runt domain proteins. Mol Cell Biol 17: 5581–5587.

32. CanonJ, BanerjeeU (2003) In vivo analysis of a developmental circuit for direct transcriptional activation and repression in the same cell by a Runx protein. Genes Dev 17: 838–843.

33. ChenH, XuZ, MeiC, YuD, SmallS (2012) A system of repressor gradients spatially organizes the boundaries of Bicoid-dependent target genes. Cell 149: 618–629.

34. HelmanA, LimB, AndreuMJ, KimY, ShestkinT, et al. (2012) RTK signaling modulates the Dorsal gradient. Development 139: 3032–3039.

35. CinnamonE, HelmanA, Ben-Haroush SchyrR, OrianA, JiménezG, et al. (2008) Multiple RTK pathways downregulate Groucho-mediated repression in Drosophila embryogenesis. Development 135: 829–837.

36. HelmanA, CinnamonE, MezumanS, HayoukaZ, Von OhlenT, et al. (2011) Phosphorylation of Groucho mediates RTK feedback inhibition and prolonged pathway target gene expression. Curr Biol 21: 1102–1110.

37. Turki-JudehW, CoureyAJ (2012) The unconserved Groucho central region is essential for viability and modulates target gene specificity. PLoS One 7: e30610.

38. CinnamonE, ParoushZ (2008) Context-dependent regulation of Groucho/TLE-mediated repression. Curr Opin Genet Dev 18: 435–440.

39. TangAH, NeufeldTP, RubinGM, MullerHA (2001) Transcriptional regulation of cytoskeletal functions and segmentation by a novel maternal pair-rule gene, lilliputian. Development 128: 801–813.

40. LuoZ, LinC, SchilatifardA (2012) The super elongation complex (SEC) family in transcriptional control. Nat Rev Mol Cell Biol 13: 543–547.

41. TsudaH, Jafar-NejadP, PatelAJ, SunY, ChenHK, et al. (2005) The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins. Cell 122: 633–644.

42. Crespo-BarretoJ, FryerJD, ShawCA, OrrHT, ZoghbiHY (2010) Partial loss of Ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis. PLoS Genet 6: e1001021.

43. ChouTB, NollE, PerrimonN (1993) Autosomal P[ovoD1] dominant female-sterile insertions in Drosophila and their use in generating germ-line chimeras. Development 119: 1359–1369.

44. BischofJ, MaedaRK, HedigerM, KarchF, BaslerK (2007) An optimized transgenesis system for Drosophila using germ-line-specific ΦC31 integrases. Proc Natl Acad Sci U S A 104: 3312–3317.

45. HousdenBE, Terriente-FelixA, BraySJ (2014) Context-dependent enhancer selection confers alternate models of notch regulation on argos. Mol Cell Biol 34: 664–672.

46. Younger-ShepherdS, VaessinH, BierE, JanLY, JanYN (1992) deadpan, an essential pan-neural gene encoding an HLH protein, acts as a denominator in Drosophila sex determination. Cell 70: 911–922.

47. GraveleyBR, BrooksA, CarlsonJW, DuffMO, LandolinJM, et al. (2011) The developmental transcriptome of Drosophila melanogaster. Nature 471: 473–479.