A Combination of Activation and Repression by a Colinear Hox Code Controls Forelimb-Restricted Expression of and Reveals Hox Protein Specificity

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The acquisition of limbs during vertebrate evolution was a very successful innovation that enabled this group of species to diversify and colonise land. It has become clear recently that the primary driver behind the evolution of new structures, such as limbs, is the acquisition of novel regulatory elements that control when and where genes are activated rather than the proteins encoded by the genes themselves acquiring novel functions. We have identified the regulatory element from a gene, Tbx5. Activation of Tbx5 in the forelimb-forming region of the developing embryos is essential for forelimbs to form and disruption of human TBX5 causes limb abnormalities. We show that activation of Tbx5 in a restricted territory is achieved through a combination of activation inputs that are present broadly throughout the embryo flank and dominant, repressive inputs present only in more caudal regions of the flank. The sum of these inputs yields restricted activation in the rostral, forelimb-forming flank. Our results explain how the regulatory switches that were harnessed for the acquisition of limbs during evolution operate and how they can be turned off during the evolution of limblessness in species such as the snake.

Vyšlo v časopise: A Combination of Activation and Repression by a Colinear Hox Code Controls Forelimb-Restricted Expression of and Reveals Hox Protein Specificity. PLoS Genet 10(3): e32767. doi:10.1371/journal.pgen.1004245
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004245

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Zdroje

1. DubocV, LoganMP (2011) Regulation of limb bud initiation and limb-type morphology. Dev Dyn 240: 1017–1027.

2. Gibson-BrownJJ, SIA, SilverLM, PapaioannouVE (1998) Expression of T-box genes Tbx2-Tbx5 during chick organogenesis. Mech Dev 74: 165–169.

3. IsaacA, Rodriguez-EstebanC, RyanA, AltabefM, TsukuiT, et al. (1998) Tbx genes and limb identity in chick embryo development. Development 125: 1867–1875.

4. LoganM, SimonHG, TabinC (1998) Differential regulation of T-box and homeobox transcription factors suggests roles in controlling chick limb-type identity. Development 125: 2825–2835.

5. OhuchiH, TakeuchiJ, YoshiokaH, IshimaruY, OguraK, et al. (1998) Correlation of wing-leg identity in ectopic FGF-induced chimeric limbs with the differential expression of chick Tbx5 and Tbx4. Development 125: 51–60.

6. RallisC, BruneauBG, Del BuonoJ, SeidmanCE, SeidmanJG, et al. (2003) Tbx5 is required for forelimb bud formation and continued outgrowth. Development 130: 2741–2751.

7. AgarwalP, WylieJN, GalceranJ, ArkhitkoO, LiC, et al. (2003) Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo. Development 130: 623–633.

8. NaicheLA, PapaioannouVE (2003) Loss of Tbx4 blocks hindlimb development and affects vascularization and fusion of the allantois. Development 130: 2681–2693.

9. LiQY, Newbury-EcobRA, TerrettJA, WilsonDI, CurtisAR, et al. (1997) Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet 15: 21–29.

10. BassonCT, BachinskyDR, LinRC, LeviT, ElkinsJA, et al. (1997) Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 15: 30–35.

11. BongersEM, DuijfPH, van BeersumSE, SchootsJ, Van KampenA, et al. (2004) Mutations in the human TBX4 gene cause small patella syndrome. Am J Hum Genet 74: 1239–1248.

12. HassonP, Del BuonoJ, LoganMP (2007) Tbx5 is dispensable for forelimb outgrowth. Development 134: 85–92.

13. MinguillonC, Del BuonoJ, LoganMP (2005) Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth. Dev Cell 8: 75–84.

14. MinguillonC, Gibson-BrownJJ, LoganMP (2009) Tbx4/5 gene duplication and the origin of vertebrate paired appendages. Proc Natl Acad Sci U S A 106: 21726–21730.

15. WellikDM (2009) Hox genes and vertebrate axial pattern. Curr Top Dev Biol 88: 257–278.

16. DubouleD (2007) The rise and fall of Hox gene clusters. Development 134: 2549–2560.

17. BurkeAC, NelsonCE, MorganBA, TabinC (1995) Hox genes and the evolution of vertebrate axial morphology. Development 121: 333–346.

18. CohnMJ, TickleC (1999) Developmental basis of limblessness and axial patterning in snakes. Nature 399: 474–479.

19. MinguillonC, NishimotoS, WoodS, VendrellE, Gibson-BrownJJ, et al. (2012) Hox genes regulate the onset of Tbx5 expression in the forelimb. Development 139: 3180–3188.

20. MannRS, AffolterM (1998) Hox proteins meet more partners. Curr Opin Genet Dev 8: 423–429.

21. LoganM, TabinCJ (1999) Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity. Science 283: 1736–1739.

22. TakeuchiJK, Koshiba-TakeuchiK, MatsumotoK, Vogel-HopkerA, Naitoh-MatsuoM, et al. (1999) Tbx5 and Tbx4 genes determine the wing/leg identity of limb buds. Nature 398: 810–814.

23. DeLaurierA, SchweitzerR, LoganM (2006) Pitx1 determines the morphology of muscle, tendon, and bones of the hindlimb. Dev Biol 299: 22–34.

24. DubocV, LoganMP (2011) Pitx1 is necessary for normal initiation of hindlimb outgrowth through regulation of Tbx4 expression and shapes hindlimb morphologies via targeted growth control. Development 138: 5301–5309.

25. BergerMF, BadisG, GehrkeAR, TalukderS, PhilippakisAA, et al. (2008) Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Cell 133: 1266–1276.

26. JoshiR, SunL, MannR (2010) Dissecting the functional specificities of two Hox proteins. Genes Dev 24: 1533–1545.

27. GordonJA, HassanMQ, SainiS, MontecinoM, van WijnenAJ, et al. (2010) Pbx1 represses osteoblastogenesis by blocking Hoxa10-mediated recruitment of chromatin remodeling factors. Mol Cell Biol 30: 3531–3541.

28. MerabetS, KambrisZ, CapovillaM, BerengerH, PradelJ, et al. (2003) The hexapeptide and linker regions of the AbdA Hox protein regulate its activating and repressive functions. Dev Cell 4: 761–768.

29. PapadopoulosDK, Resendez-PerezD, Cardenas-ChavezDL, Villanueva-SeguraK, Canales-del-CastilloR, et al. (2011) Functional synthetic Antennapedia genes and the dual roles of YPWM motif and linker size in transcriptional activation and repression. Proc Natl Acad Sci U S A 108: 11959–11964.

30. LuY, GoldenbergI, BeiL, AndrejicJ, EklundEA (2003) HoxA10 represses gene transcription in undifferentiated myeloid cells by interaction with histone deacetylase 2. J Biol Chem 278: 47792–47802.

31. WalshCM, CarrollSB (2007) Collaboration between Smads and a Hox protein in target gene repression. Development 134: 3585–3592.

32. LelliKM, NoroB, MannRS (2011) Variable motif utilization in homeotic selector (Hox)-cofactor complex formation controls specificity. Proc Natl Acad Sci U S A 108: 21122–21127.

33. FujiokaM, GebeleinB, CoferZC, MannRS, JaynesJB (2012) Engrailed cooperates directly with Extradenticle and Homothorax on a distinct class of homeodomain binding sites to repress sloppy paired. Dev Biol 366: 382–392.

34. GebeleinB, McKayDJ, MannRS (2004) Direct integration of Hox and segmentation gene inputs during Drosophila development. Nature 431: 653–659.

35. WurstW, AuerbachAB, JoynerAL (1994) Multiple developmental defects in Engrailed-1 mutant mice: an early mid-hindbrain deletion and patterning defects in forelimbs and sternum. Development 120: 2065–2075.

36. BroccoliV, ColomboE, CossuG (2002) Dmbx1 is a paired-box containing gene specifically expressed in the caudal most brain structures. Mech Dev 114: 219–223.

37. FilosaS, Rivera-PerezJA, GomezAP, GansmullerA, SasakiH, et al. (1997) Goosecoid and HNF-3beta genetically interact to regulate neural tube patterning during mouse embryogenesis. Development 124: 2843–2854.

38. CohnMJ, PatelK, KrumlaufR, WilkinsonDG, ClarkeJD, et al. (1997) Hox9 genes and vertebrate limb specification. Nature 387: 97–101.

39. CohnMJ, Izpisua-BelmonteJC, AbudH, HeathJK, TickleC (1995) Fibroblast growth factors induce additional limb development from the flank of chick embryos. Cell 80: 739–746.

40. XuB, WellikDM (2011) Axial Hox9 activity establishes the posterior field in the developing forelimb. Proc Natl Acad Sci U S A 108: 4888–4891.

41. SuemoriH, NoguchiS (2000) Hox C cluster genes are dispensable for overall body plan of mouse embryonic development. Dev Biol 220: 333–342.

42. StrickerS, BrieskeN, HauptJ, MundlosS (2006) Comparative expression pattern of Odd-skipped related genes Osr1 and Osr2 in chick embryonic development. Gene Expr Patterns 6: 826–834.

43. ChanSK, MannRS (1993) The segment identity functions of Ultrabithorax are contained within its homeo domain and carboxy-terminal sequences. Genes Dev 7: 796–811.

44. GebeleinB, CuliJ, RyooHD, ZhangW, MannRS (2002) Specificity of Distalless repression and limb primordia development by abdominal Hox proteins. Dev Cell 3: 487–498.

45. NoroB, LelliK, SunL, MannRS (2011) Competition for cofactor-dependent DNA binding underlies Hox phenotypic suppression. Genes Dev 25: 2327–2332.

46. Furukubo-TokunagaK, FlisterS, GehringWJ (1993) Functional specificity of the Antennapedia homeodomain. Proc Natl Acad Sci U S A 90: 6360–6364.

47. LinL, McGinnisW (1992) Mapping functional specificity in the Dfd and Ubx homeo domains. Genes Dev 6: 1071–1081.

48. RyooHD, MannRS (1999) The control of trunk Hox specificity and activity by Extradenticle. Genes Dev 13: 1704–1716.

49. SummerbellD, AshbyPR, CoutelleO, CoxD, YeeS, et al. (2000) The expression of Myf5 in the developing mouse embryo is controlled by discrete and dispersed enhancers specific for particular populations of skeletal muscle precursors. Development 127: 3745–3757.

50. Kaufman MH (2001) The Atlas of Mouse Development, 2nd edn. Cambridge, UK: Academic Press.

51. RiddleRD, JohnsonRL, LauferE, TabinC (1993) Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75: 1401–1416.

52. NelsonCE, MorganBA, BurkeAC, LauferE, DiMambroE, et al. (1996) Analysis of Hox gene expression in the chick limb bud. Development 122: 1449–1466.

53. PetersonRL, PapenbrockT, DavdaMM, AwgulewitschA (1994) The murine Hoxc cluster contains five neighboring AbdB-related Hox genes that show unique spatially coordinated expression in posterior embryonic subregions. Mech Dev 47: 253–260.

54. HamburgerV, HamiltonHL (1992) A series of normal stages in the development of the chick embryo. 1951. Dev Dyn 195: 231–272.