Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes and

English version České info

Vertebrate organ development relies on the precise spatiotemporal orchestration of proliferation rates and differentiation patterns in adjacent tissue compartments. The underlying integration of patterning and cell cycle control during organogenesis is insufficiently understood. Here, we have investigated the function of the patterning T-box transcription factor gene Tbx2 in lung development. We show that lungs of Tbx2-deficient mice are markedly hypoplastic and exhibit reduced branching morphogenesis. Mesenchymal proliferation was severely decreased, while mesenchymal differentiation into fibrocytes was prematurely induced. In the epithelial compartment, proliferation was reduced and differentiation of alveolar epithelial cells type 1 was compromised. Prior to the observed cellular changes, canonical Wnt signaling was downregulated, and Cdkn1a (p21) and Cdkn1b (p27) (two members of the Cip/Kip family of cell cycle inhibitors) were strongly induced in the Tbx2-deficient lung mesenchyme. Deletion of both Cdkn1a and Cdkn1b rescued, to a large degree, the growth deficits of Tbx2-deficient lungs. Prolongation of Tbx2 expression into adulthood led to hyperproliferation and maintenance of mesenchymal progenitor cells, with branching morphogenesis remaining unaffected. Expression of Cdkn1a and Cdkn1b was ablated from the lung mesenchyme in this gain-of-function setting. We further show by ChIP experiments that Tbx2 directly binds to Cdkn1a and Cdkn1b loci in vivo, defining these two genes as direct targets of Tbx2 repressive activity in the lung mesenchyme. We conclude that Tbx2-mediated regulation of Cdkn1a and Cdkn1b represents a crucial node in the network integrating patterning information and cell cycle regulation that underlies growth, differentiation, and branching morphogenesis of this organ.

Vyšlo v časopise: Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes and. PLoS Genet 9(1): e32767. doi:10.1371/journal.pgen.1003189
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003189

Souhrn

Zdroje

1. SherrCJ, RobertsJM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13: 1501–1512.

2. VidalA, KoffA (2000) Cell-cycle inhibitors: three families united by a common cause. Gene 247: 1–15.

3. BessonA, DowdySF, RobertsJM (2008) CDK inhibitors: cell cycle regulators and beyond. Dev Cell 14: 159–169.

4. NaicheLA, HarrelsonZ, KellyRG, PapaioannouVE (2005) T-box genes in vertebrate development. Annu Rev Genet 39: 219–239.

5. DavenportTG, Jerome-MajewskaLA, PapaioannouVE (2003) Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Development 130: 2263–2273.

6. HarrelsonZ, KellyRG, GoldinSN, Gibson-BrownJJ, BollagRJ, et al. (2004) Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development. Development 131: 5041–5052.

7. SuzukiA, SekiyaS, BuscherD, Izpisua BelmonteJC, TaniguchiH (2008) Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19ARF expression. Development 135: 1589–1595.

8. LudtkeTH, ChristoffelsVM, PetryM, KispertA (2009) Tbx3 promotes liver bud expansion during mouse development by suppression of cholangiocyte differentiation. Hepatology 49: 969–978.

9. ZirzowS, LudtkeTH, BronsJF, PetryM, ChristoffelsVM, et al. (2009) Expression and requirement of T-box transcription factors Tbx2 and Tbx3 during secondary palate development in the mouse. Dev Biol 336: 145–155.

10. SinghR, HoogaarsWM, BarnettP, GrieskampT, RanaMS, et al. (2012) Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation. Cell Mol Life Sci 69: 1377–1389.

11. JacobsJJ, KeblusekP, Robanus-MaandagE, KristelP, LingbeekM, et al. (2000) Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers. Nat Genet 26: 291–299.

12. PrinceS, CarreiraS, VanceKW, AbrahamsA, GodingCR (2004) Tbx2 directly represses the expression of the p21(WAF1) cyclin-dependent kinase inhibitor. Cancer Res 64: 1669–1674.

13. VanceKW, CarreiraS, BroschG, GodingCR (2005) Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas. Cancer Res 65: 2260–2268.

14. LuJ, LiXP, DongQ, KungHF, HeML (2010) TBX2 and TBX3: the special value for anticancer drug targets. Biochim Biophys Acta 1806: 268–274.

15. AbrahamsA, ParkerMI, PrinceS (2009) The T-box transcription factor Tbx2: its role in development and possible implication in cancer. IUBMB Life 62: 92–102.

16. LingbeekME, JacobsJJ, van LohuizenM (2002) The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator. J Biol Chem 277: 26120–26127.

17. HoogaarsWM, BarnettP, RodriguezM, CloutDE, MoormanAF, et al. (2008) TBX3 and its splice variant TBX3 + exon 2a are functionally similar. Pigment Cell Melanoma Res 21: 379–387.

18. MorriseyEE, HoganBL (2010) Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev Cell 18: 8–23.

19. Cebra-ThomasJA, BromerJ, GardnerR, LamGK, SheipeH, et al. (2003) T-box gene products are required for mesenchymal induction of epithelial branching in the embryonic mouse lung. Dev Dyn 226: 82–90.

20. ChapmanDL, GarveyN, HancockS, AlexiouM, AgulnikSI, et al. (1996) Expression of the T-box family genes, Tbx1–Tbx5, during early mouse development. Dev Dyn 206: 379–390.

21. AanhaanenWT, BronsJF, DominguezJN, RanaMS, NordenJ, et al. (2009) The Tbx2+ primary myocardium of the atrioventricular canal forms the atrioventricular node and the base of the left ventricle. Circ Res 104: 1267–1274.

22. RajagopalJ, CarrollTJ, GusehJS, BoresSA, BlankLJ, et al. (2008) Wnt7b stimulates embryonic lung growth by coordinately increasing the replication of epithelium and mesenchyme. Development 135: 1625–1634.

23. LiuY, HoganBL (2002) Differential gene expression in the distal tip endoderm of the embryonic mouse lung. Gene Expr Patterns 2: 229–233.

24. OkuboT, KnoepflerPS, EisenmanRN, HoganBL (2005) Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation. Development 132: 1363–1374.

25. GontanC, de MunckA, VermeijM, GrosveldF, TibboelD, et al. (2008) Sox2 is important for two crucial processes in lung development: branching morphogenesis and epithelial cell differentiation. Dev Biol 317: 296–309.

26. IshiiY, RexM, ScottingPJ, YasugiS (1998) Region-specific expression of chicken Sox2 in the developing gut and lung epithelium: regulation by epithelial-mesenchymal interactions. Dev Dyn 213: 464–475.

27. MorganSM, SamulowitzU, DarleyL, SimmonsDL, VestweberD (1999) Biochemical characterization and molecular cloning of a novel endothelial-specific sialomucin. Blood 93: 165–175.

28. LawsonWE, PolosukhinVV, ZoiaO, StathopoulosGT, HanW, et al. (2005) Characterization of fibroblast-specific protein 1 in pulmonary fibrosis. Am J Respir Crit Care Med 171: 899–907.

29. PaxsonJA, ParkinCD, IyerLK, MazanMR, IngenitoEP, et al. (2009) Global gene expression patterns in the post-pneumonectomy lung of adult mice. Respir Res 10: 92.

30. Kaarteenaho-WiikR, PaakkoP, SormunenR (2009) Ultrastructural features of lung fibroblast differentiation into myofibroblasts. Ultrastruct Pathol 33: 6–15.

31. GompertsBN, StrieterRM (2007) Fibrocytes in lung disease. J Leukoc Biol 82: 449–456.

32. ShimazakiM, NakamuraK, KiiI, KashimaT, AmizukaN, et al. (2008) Periostin is essential for cardiac healing after acute myocardial infarction. J Exp Med 205: 295–303.

33. AroraR, MetzgerRJ, PapaioannouVE (2012) Multiple roles and interactions of Tbx4 and Tbx5 in development of the respiratory system. PLoS Genet 8: e1002866 doi:10.1371/journal.pgen.1002866.

34. 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.

35. HabetsPE, MoormanAF, CloutDE, van RoonMA, LingbeekM, et al. (2002) Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Genes Dev 16: 1234–1246.

36. MaedaR, KobayashiA, SekineR, LinJJ, KungH, et al. (1997) Xmsx-1 modifies mesodermal tissue pattern along dorsoventral axis in Xenopus laevis embryo. Development 124: 2553–2560.

37. GoodrichLV, JohnsonRL, MilenkovicL, McMahonJA, ScottMP (1996) Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev 10: 301–312.

38. JhoEH, ZhangT, DomonC, JooCK, FreundJN, et al. (2002) Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 22: 1172–1183.

39. MunchbergSR, SteinbeisserH (1999) The Xenopus Ets transcription factor XER81 is a target of the FGF signaling pathway. Mech Dev 80: 53–65.

40. TetsuO, McCormickF (1999) Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398: 422–426.

41. KispertA, HerrmannBG (1993) The Brachyury gene encodes a novel DNA binding protein. EMBO J 12: 3211–3220.

42. LucheH, WeberO, Nageswara RaoT, BlumC, FehlingHJ (2007) Faithful activation of an extra-bright red fluorescent protein in “knock-in” Cre-reporter mice ideally suited for lineage tracing studies. Eur J Immunol 37: 43–53.

43. StarostinaNG, KipreosET (2012) Multiple degradation pathways regulate versatile CIP/KIP CDK inhibitors. Trends Cell Biol 22: 33–41.

44. ZhangP, LiegeoisNJ, WongC, FinegoldM, HouH, et al. (1997) Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature 387: 151–158.

45. YanY, FrisenJ, LeeMH, MassagueJ, BarbacidM (1997) Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. Genes Dev 11: 973–983.

46. HolsbergerDR, BucholdGM, LealMC, KiesewetterSE, O'BrienDA, et al. (2005) Cell-cycle inhibitors p27Kip1 and p21Cip1 regulate murine Sertoli cell proliferation. Biol Reprod 72: 1429–1436.

47. OkahashiN, MuraseY, KosekiT, SatoT, YamatoK, et al. (2001) Osteoclast differentiation is associated with transient upregulation of cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(KIP1). J Cell Biochem 80: 339–345.

48. el-DeiryWS, TokinoT, VelculescuVE, LevyDB, ParsonsR, et al. (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817–825.

49. GartelAL, TynerAL (1999) Transcriptional regulation of the p21((WAF1/CIP1)) gene. Exp Cell Res 246: 280–289.

50. BlintE, PhillipsAC, KozlovS, StewartCL, VousdenKH (2002) Induction of p57(KIP2) expression by p73beta. Proc Natl Acad Sci U S A 99: 3529–3534.

51. GeorgiaS, SolizR, LiM, ZhangP, BhushanA (2006) p57 and Hes1 coordinate cell cycle exit with self-renewal of pancreatic progenitors. Dev Biol 298: 22–31.

52. VaccarelloG, FigliolaR, CramerottiS, NovelliF, MaioneR (2006) p57Kip2 is induced by MyoD through a p73-dependent pathway. J Mol Biol 356: 578–588.

53. van den BoogaardM, WongLY, TessadoriF, BakkerML, DreizehnterLK, et al. (2012) Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer. J Clin Invest 122: 2519–2530.

54. TanakaH, YamashitaT, AsadaM, MizutaniS, YoshikawaH, et al. (2002) Cytoplasmic p21(Cip1/WAF1) regulates neurite remodeling by inhibiting Rho-kinase activity. J Cell Biol 158: 321–329.

55. ZhangP, WongC, DePinhoRA, HarperJW, ElledgeSJ (1998) Cooperation between the Cdk inhibitors p27(KIP1) and p57(KIP2) in the control of tissue growth and development. Genes Dev 12: 3162–3167.

56. EblaghieMC, ReedyM, OliverT, MishinaY, HoganBL (2006) Evidence that autocrine signaling through Bmpr1a regulates the proliferation, survival and morphogenetic behavior of distal lung epithelial cells. Dev Biol 291: 67–82.

57. LiC, XiaoJ, HormiK, BorokZ, MinooP (2002) Wnt5a participates in distal lung morphogenesis. Dev Biol 248: 68–81.

58. GossAM, TianY, TsukiyamaT, CohenED, ZhouD, et al. (2009) Wnt2/2b and beta-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut. Dev Cell 17: 290–298.

59. GossAM, TianY, ChengL, YangJ, ZhouD, et al. (2011) Wnt2 signaling is necessary and sufficient to activate the airway smooth muscle program in the lung by regulating myocardin/Mrtf-B and Fgf10 expression. Dev Biol 356: 541–552.

60. ShuW, GuttentagS, WangZ, AndlT, BallardP, et al. (2005) Wnt/beta-catenin signaling acts upstream of N-myc, BMP4, and FGF signaling to regulate proximal-distal patterning in the lung. Dev Biol 283: 226–239.

61. YinY, WhiteAC, HuhSH, HiltonMJ, KanazawaH, et al. (2008) An FGF-WNT gene regulatory network controls lung mesenchyme development. Dev Biol 319: 426–436.

62. ShtutmanM, ZhurinskyJ, SimchaI, AlbaneseC, D'AmicoM, et al. (1999) The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A 96: 5522–5527.

63. BrugarolasJ, ChandrasekaranC, GordonJI, BeachD, JacksT, et al. (1995) Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377: 552–557.

64. FeroML, RivkinM, TaschM, PorterP, CarowCE, et al. (1996) A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell 85: 733–744.

65. YoungP, BoussadiaO, HalfterH, GroseR, BergerP, et al. (2003) E-cadherin controls adherens junctions in the epidermis and the renewal of hair follicles. EMBO J 22: 5723–5733.

66. BrachtendorfG, KuhnA, SamulowitzU, KnorrR, GustafssonE, et al. (2001) Early expression of endomucin on endothelium of the mouse embryo and on putative hematopoietic clusters in the dorsal aorta. Dev Dyn 222: 410–419.

67. WilkinsonDG, NietoMA (1993) Detection of messenger RNA by in situ hybridization to tissue sections and whole mounts. Methods Enzymol 225: 361–373.

68. MoormanAF, HouwelingAC, de BoerPA, ChristoffelsVM (2001) Sensitive nonradioactive detection of mRNA in tissue sections: novel application of the whole-mount in situ hybridization protocol. J Histochem Cytochem 49: 1–8.

69. BussenM, PetryM, Schuster-GosslerK, LeitgesM, GosslerA, et al. (2004) The T-box transcription factor Tbx18 maintains the separation of anterior and posterior somite compartments. Genes Dev 18: 1209–1221.

70. BraunsteinM, RoseAB, HolmesSG, AllisCD, BroachJR (1993) Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev 7: 592–604.