#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Tbx2 Terminates Shh/Fgf Signaling in the Developing Mouse Limb Bud by Direct Repression of


Vertebrate limb outgrowth is driven by a positive feedback loop that involves Sonic hedgehog (Shh) and Gremlin1 (Grem1) in the posterior limb bud mesenchyme and Fibroblast growth factors (Fgfs) in the overlying epithelium. Proper spatio-temporal control of these signaling activities is required to avoid limb malformations such as polydactyly. Here we show that, in Tbx2-deficient hindlimbs, Shh/Fgf4 signaling is prolonged, resulting in increased limb bud size and duplication of digit 4. In turn, limb-specific Tbx2 overexpression leads to premature termination of this signaling loop with smaller limbs and reduced digit number as phenotypic manifestation. We show that Tbx2 directly represses Grem1 in distal regions of the posterior limb mesenchyme allowing Bone morphogenetic protein (Bmp) signaling to abrogate Fgf4/9/17 expression in the overlying epithelium. Since Tbx2 itself is a target of Bmp signaling, our data identify a growth-inhibiting positive feedback loop (Bmp/Tbx2/Grem1). We propose that proliferative expansion of Tbx2-expressing cells mediates self-termination of limb bud outgrowth due to their refractoriness to Grem1 induction.


Vyšlo v časopise: Tbx2 Terminates Shh/Fgf Signaling in the Developing Mouse Limb Bud by Direct Repression of. PLoS Genet 9(4): e32767. doi:10.1371/journal.pgen.1003467
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003467

Souhrn

Vertebrate limb outgrowth is driven by a positive feedback loop that involves Sonic hedgehog (Shh) and Gremlin1 (Grem1) in the posterior limb bud mesenchyme and Fibroblast growth factors (Fgfs) in the overlying epithelium. Proper spatio-temporal control of these signaling activities is required to avoid limb malformations such as polydactyly. Here we show that, in Tbx2-deficient hindlimbs, Shh/Fgf4 signaling is prolonged, resulting in increased limb bud size and duplication of digit 4. In turn, limb-specific Tbx2 overexpression leads to premature termination of this signaling loop with smaller limbs and reduced digit number as phenotypic manifestation. We show that Tbx2 directly represses Grem1 in distal regions of the posterior limb mesenchyme allowing Bone morphogenetic protein (Bmp) signaling to abrogate Fgf4/9/17 expression in the overlying epithelium. Since Tbx2 itself is a target of Bmp signaling, our data identify a growth-inhibiting positive feedback loop (Bmp/Tbx2/Grem1). We propose that proliferative expansion of Tbx2-expressing cells mediates self-termination of limb bud outgrowth due to their refractoriness to Grem1 induction.


Zdroje

1. ZellerR, Lopez-RiosJ, ZunigaA (2009) Vertebrate limb bud development: moving towards integrative analysis of organogenesis. Nat Rev Genet 10: 845–858.

2. MarianiFV, AhnCP, MartinGR (2008) Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning. Nature 453: 401–405.

3. ZhuJ, NakamuraE, NguyenMT, BaoX, AkiyamaH, et al. (2008) Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud. Dev Cell 14: 624–632.

4. SummerbellD (1974) A quantitative analysis of the effect of excision of the AER from the chick limb-bud. J Embryol Exp Morphol 32: 651–660.

5. ChiangC, LitingtungY, HarrisMP, SimandlBK, LiY, et al. (2001) Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. Dev Biol 236: 421–435.

6. SunX, MarianiFV, MartinGR (2002) Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature 418: 501–508.

7. HarfeBD, ScherzPJ, NissimS, TianH, McMahonAP, et al. (2004) Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell 118: 517–528.

8. LauferE, NelsonCE, JohnsonRL, MorganBA, TabinC (1994) Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell 79: 993–1003.

9. NiswanderL, JeffreyS, MartinGR, TickleC (1994) A positive feedback loop coordinates growth and patterning in the vertebrate limb. Nature 371: 609–612.

10. BenazetJD, BischofbergerM, TieckeE, GoncalvesA, MartinJF, et al. (2009) A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning. Science 323: 1050–1053.

11. ZunigaA, HaramisAP, McMahonAP, ZellerR (1999) Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds. Nature 401: 598–602.

12. KhokhaMK, HsuD, BrunetLJ, DionneMS, HarlandRM (2003) Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning. Nat Genet 34: 303–307.

13. MichosO, PanmanL, VinterstenK, BeierK, ZellerR, et al. (2004) Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis. Development 131: 3401–3410.

14. Lopez-RiosJ, SpezialeD, RobayD, ScottiM, OsterwalderM, et al. (2012) GLI3 constrains digit number by controlling both progenitor proliferation and BMP-dependent exit to chondrogenesis. Dev Cell 22: 837–848.

15. ScherzPJ, HarfeBD, McMahonAP, TabinCJ (2004) The limb bud Shh-Fgf feedback loop is terminated by expansion of former ZPA cells. Science 305: 396–399.

16. 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.

17. 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.

18. 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.

19. SuzukiT, TakeuchiJ, Koshiba-TakeuchiK, OguraT (2004) Tbx Genes Specify Posterior Digit Identity through Shh and BMP Signaling. Dev Cell 6: 43–53.

20. RallisC, Del BuonoJ, LoganMP (2005) Tbx3 can alter limb position along the rostrocaudal axis of the developing embryo. Development 132: 1961–1970.

21. 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.

22. WrightE, HargraveMR, ChristiansenJ, CooperL, KunJ, et al. (1995) The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos. Nat Genet 9: 15–20.

23. NiederreitherK, McCafferyP, DragerUC, ChambonP, DolleP (1997) Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mech Dev 62: 67–78.

24. Salas-VidalE, ValenciaC, CovarrubiasL (2001) Differential tissue growth and patterns of cell death in mouse limb autopod morphogenesis. Dev Dyn 220: 295–306.

25. VerheydenJM, LewandoskiM, DengC, HarfeBD, SunX (2005) Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning. Development 132: 4235–4245.

26. MaoJ, McGlinnE, HuangP, TabinCJ, McMahonAP (2009) Fgf-dependent Etv4/5 activity is required for posterior restriction of Sonic Hedgehog and promoting outgrowth of the vertebrate limb. Dev Cell 16: 600–606.

27. HancockSN, AgulnikSI, SilverLM, PapaioannouVE (1999) Mapping and expression analysis of the mouse ortholog of Xenopus Eomesodermin. Mech Dev 81: 205–208.

28. CarreiraS, DexterTJ, YavuzerU, EastyDJ, GodingCR (1998) Brachyury-related transcription factor Tbx2 and repression of the melanocyte-specific TRP-1 promoter. Mol Cell Biol 18: 5099–5108.

29. GrotewoldL, RutherU (2002) The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death. EMBO J 21: 966–975.

30. PizetteS, Abate-ShenC, NiswanderL (2001) BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb. Development 128: 4463–4474.

31. VokesSA, JiH, WongWH, McMahonAP (2008) A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb. Genes Dev 22: 2651–2663.

32. MaL, LuMF, SchwartzRJ, MartinJF (2005) Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development 132: 5601–5611.

33. BehestiH, HoltJK, SowdenJC (2006) The level of BMP4 signaling is critical for the regulation of distinct T-box gene expression domains and growth along the dorso-ventral axis of the optic cup. BMC Dev Biol 6: 62.

34. SinghR, HorsthuisT, FarinHF, GrieskampT, NordenJ, et al. (2009) Tbx20 interacts with smads to confine tbx2 expression to the atrioventricular canal. Circ Res 105: 442–452.

35. ShiraiM, Imanaka-YoshidaK, SchneiderMD, SchwartzRJ, MorisakiT (2009) T-box 2, a mediator of Bmp-Smad signaling, induced hyaluronan synthase 2 and Tgfbeta2 expression and endocardial cushion formation. Proc Natl Acad Sci U S A 106: 18604–18609.

36. YuPB, HongCC, SachidanandanC, BabittJL, DengDY, et al. (2008) Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol 4: 33–41.

37. SinghR, HoogaarsWM, BarnettP, GrieskampT, RanaMS, et al. (2011) Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation. Cell Mol Life Sci 69: 1377–1389.

38. LoganM, MartinJF, NagyA, LobeC, OlsonEN, et al. (2002) Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis 33: 77–80.

39. MinowadaG, JarvisLA, ChiCL, NeubuserA, SunX, et al. (1999) Vertebrate Sprouty genes are induced by FGF signaling and can cause chondrodysplasia when overexpressed. Development 126: 4465–4475.

40. 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.

41. RoehlH, Nusslein-VolhardC (2001) Zebrafish pea3 and erm are general targets of FGF8 signaling. Curr Biol 11: 503–507.

42. NissimS, HassoSM, FallonJF, TabinCJ (2006) Regulation of Gremlin expression in the posterior limb bud. Dev Biol 299: 12–21.

43. VerheydenJM, SunX (2008) An Fgf/Gremlin inhibitory feedback loop triggers termination of limb bud outgrowth. Nature 454: 638–641.

44. SeleverJ, LiuW, LuMF, BehringerRR, MartinJF (2004) Bmp4 in limb bud mesoderm regulates digit pattern by controlling AER development. Dev Biol 276: 268–279.

45. NissimS, AllardP, BandyopadhyayA, HarfeBD, TabinCJ (2007) Characterization of a novel ectodermal signaling center regulating Tbx2 and Shh in the vertebrate limb. Dev Biol 304: 9–21.

46. Gibson-BrownJJ, AgulnikSI, SilverLM, NiswanderL, PapaioannouVE (1998) Involvement of T-box genes Tbx2-Tbx5 in vertebrate limb specification and development. Development 125: 2499–2509.

47. BandyopadhyayA, TsujiK, CoxK, HarfeBD, RosenV, et al. (2006) Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet 2: e216 doi:10.1371/journal.pgen.0020216.

48. MukhopadhyayM, ShtromS, Rodriguez-EstebanC, ChenL, TsukuiT, et al. (2001) Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Dev Cell 1: 423–434.

49. PorettiA, VitielloG, HennekamRC, ArrigoniF, BertiniE, et al. (2012) Delineation and diagnostic criteria of Oral-Facial-Digital Syndrome type VI. Orphanet J Rare Dis 7: 4.

50. HsiehYC, HouJW (1999) Oral-facial-digital syndrome with Y-shaped fourth metacarpals and endocardial cushion defect. Am J Med Genet 86: 278–281.

51. 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.

52. 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.

53. HochRV, SorianoP (2006) Context-specific requirements for Fgfr1 signaling through Frs2 and Frs3 during mouse development. Development 133: 663–673.

54. SorianoP (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21: 70–71.

55. NovakA, GuoC, YangW, NagyA, LobeCG (2000) Z/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon Cre-mediated excision. Genesis 28: 147–155.

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

57. 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.

58. 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.

59. LüdtkeTH-W, FarinHF, RudatC, Schuster-GosslerK, PetryM, et al. (2012) Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes Cdkn1a and Cdkn1b. PLoS Genet 9: e1003189 doi:10.1371/journal.pgen.1003189.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2013 Číslo 4
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#