Development Genes and Evolution

, Volume 218, Issue 11–12, pp 667–680 | Cite as

The amphioxus genome enlightens the evolution of the thyroid hormone signaling pathway

  • Mathilde Paris
  • Frédéric Brunet
  • Gabriel V. Markov
  • Michael Schubert
  • Vincent Laudet
Original Article

Abstract

Thyroid hormones (THs) have pleiotropic effects on vertebrate development, with amphibian metamorphosis as the most spectacular example. However, developmental functions of THs in non-vertebrate chordates are largely hypothetical and even TH endogenous production has been poorly investigated. In order to get better insight into the evolution of the thyroid hormone signaling pathway in chordates, we have taken advantage of the recent release of the amphioxus genome. We found amphioxus homologous sequences to most of the genes encoding proteins involved in thyroid hormone signaling in vertebrates, except the fast-evolving thyroglobulin: sodium iodide symporter, thyroid peroxidase, deiodinases, thyroid hormone receptor, TBG, and CTHBP. As only some genes encoding proteins involved in TH synthesis regulation were retrieved (TRH, TSH receptor, and CRH receptor but not their corresponding receptors and ligands), there may be another mode of upstream regulation of TH synthesis in amphioxus. In accord with the notion that two whole genome duplications took place at the base of the vertebrate tree, one amphioxus gene often corresponded to several vertebrate homologs. However, some amphioxus specific duplications occurred, suggesting that several steps of the TH pathway were independently elaborated in the cephalochordate and vertebrate lineages. The present results therefore indicate that amphioxus is capable of producing THs. As several genes of the TH signaling pathway were also found in the sea urchin genome, we propose that the thyroid hormone signaling pathway is of ancestral origin in chordates, if not in deuterostomes, with specific elaborations in each lineage, including amphioxus.

Keywords

Branchiostoma floridae Cephalochordate Chordate Development Evolution Thyroid hormone Endostyle 

Supplementary material

427_2008_255_MOESM1_ESM.doc (70 kb)
Table S1Summary of amphioxus genes discussed in this study. (DOC 70.5 KB)
427_2008_255_MOESM2_ESM.doc (394 kb)
Table S2Summary of the other genes used in this study. (DOC 394 KB)
427_2008_255_MOESM3_ESM.doc (36 kb)
Table S3Comparison of evolutionary rates for the vertebrate peroxidases families. (DOC 35.5 KB)
427_2008_255_Fig1_ESM.gif (81 kb)
Fig. S1

Phylogenetic tree of SIS and related protein sequences. A maximum likelihood (ML) tree was obtained from analysis of SIS amino acid sequences. Bootstrap percentages obtained after 1,000 replicates are shown. The amphioxus sequences have been boxed in red. Sequences from lampreys are indicated with a large blue arrowhead and sequences from cartilaginous fishes are indicated with a narrow green arrowhead. A similar tree without sequences from basal vertebrates is shown in Fig. 2. The scale bar indicates the number of changes per site.(GIF 82 KB)

427_2008_255_Fig1_ESM.eps (450 kb)
High resolution image file (EPS 450 KB)
427_2008_255_Fig2_ESM.gif (81 kb)
Fig. S2

Phylogenetic tree of PERT and related protein sequences. A maximum likelihood (ML) tree was obtained from analysis of peroxidase amino acid sequences. Bootstrap percentages obtained after 1,000 replicates are shown. The amphioxus sequences are boxed in red. Sequences from lampreys are indicated with a large blue arrowhead and sequences from cartilaginous fishes are indicated with a narrow green arrowhead. A similar tree without sequences from basal vertebrates is shown in Fig. 3. PGH: Prostaglandin G/H synthase. The scale bar indicates the number of changes per site (GIF 82 KB)

427_2008_255_Fig2_ESM.eps (439 kb)
High resolution image file (EPS 438 KB)
427_2008_255_Fig3_ESM.gif (42 kb)
Fig. S3

Phylogenetic and structural analyses of putative deiodinases in amphioxus. a A maximum likelihood (ML) tree was obtained from analysis of deiodinase amino acid sequences. As no outgroup was found for deiodinases, the tree is presented unrooted. Bootstrap percentages obtained after 1000 replicates are shown. The amphioxus sequences have been circled in red. Sequences from lampreys are indicated with a large blue arrowhead and sequences from cartilaginous fishes are indicated with a narrow green arrowhead. The scale bar indicates the number of changes per site. A similar tree without sequences from basal vertebrates is shown in Fig. 3a. b Amino acid sequence alignment of the active catalytic domain of deiodinases from different animals (human and invertebrates). The site of a selenocysteine is shown in red. In human and H. roretzi, the translation of the TGA codon into a selenocysteine has been experimentally verified and is shown in bold (Berry et al. 1991; Curcio et al. 2001; Baqui et al. 2003). In the C. milii, S. acanthias, and L. erinacea, amphioxus and sea urchin sequences, the homologous TGA is proposed to be translated into a selenocysteine as well (italicized). (GIF 43 KB)

427_2008_255_Fig3_ESM.eps (523 kb)
High resolution image file (EPS 535 KB)
427_2008_255_Fig4_ESM.gif (123 kb)
Fig. S4

Phylogenetic tree of serpin protein sequences, including TBG. A maximum likelihood (ML) tree was obtained from analysis of serpin amino acid sequences excluding (a) or including (b) basal vertebrates. Bootstrap percentages obtained after 1,000 replicates are shown. Nodes with bootstrap support below 50% were collapsed in a. Sequences from lampreys are indicated with a large blue arrowhead and sequences from cartilaginous fishes are indicated with a narrow green arrowhead in b. The amphioxus sequences have been boxed in red and the sea urchin-specific duplications are highlighted in green. The scale bar indicates the number of changes per site. (GIF 126 KB)

427_2008_255_Fig4_ESM.eps (630 kb)
(EPS 645 KB)
427_2008_255_Fig5_ESM.gif (73 kb)
Fig. S5

Phylogenetic tree of CTHBP and related protein sequences. A maximum likelihood (ML) tree was obtained from analysis of CTHBP amino acid sequences excluding (a) or including (b) basal vertebrates. Bootstrap percentages obtained after 1,000 replicates are shown. Nodes with bootstrap support below 50% were collapsed in a. Sequences from lampreys are indicated with a large blue arrowhead and sequences from cartilaginous fishes are indicated with a narrow green arrowhead in b. The amphioxus sequences are boxed in red. The scale bar indicates the number of changes per site. (GIF 74 KB)

427_2008_255_Fig5_ESM.eps (357 kb)
(EPS 365 KB)
427_2008_255_Fig6_ESM.gif (37 kb)
Fig. S6

Phylogenetic tree of TR protein sequences, from Paris et al. (2008). A maximum likelihood (ML) tree was obtained from analysis of amino acid sequences of TR genes. Bootstrap percentages obtained after 1,000 replicates are shown. Nodes with bootstrap support below 50% were collapsed. Sequences from lamprey are indicated with a large blue arrowhead whereas sequences from the chondrichthyes S. canicula are indicated with a narrow green arrowhead. The amphioxus TR is highlighted in red. The scale bar indicates the number of changes per site. (GIF 74 KB)

427_2008_255_Fig6_ESM.eps (410 kb)
(EPS 419 KB)
427_2008_255_Fig7_ESM.gif (78 kb)
Fig. S7

Phylogenetic tree of CRHR and related protein sequences. A maximum likelihood (ML) tree was obtained from analysis of CFHR amino acid sequences excluding (a) or including (b) basal vertebrates. Bootstrap percentages obtained after 1,000 replicates are shown. Nodes with bootstrap support below 50% were collapsed in a. Sequences from lampreys are indicated with a large blue arrowhead and sequences from cartilaginous fishes are indicated with a narrow green arrowhead in b. The amphioxus sequences are highlighted in red. The scale bar indicates the number of changes per site. (GIF 79 KB)

427_2008_255_Fig7_ESM.eps (497 kb)
(EPS 509 KB)
427_2008_255_Fig8_ESM.gif (40 kb)
Fig. S8

Phylogenetic tree of TSHR and related protein sequences. A maximum likelihood (ML) tree was obtained from analysis of TSHR amino acid sequences excluding (a) or including (b) basal vertebrates. Nodes with bootstrap support below 50% were collapsed in a. Sequences from lampreys are indicated with a large blue arrowhead and sequences from cartilaginous fishes are indicated with a narrow green arrowhead in b. Bootstrap percentages obtained after 1,000 replicates are shown. The amphioxus sequence is highlighted in red. TSHR: Thyroid stimulating hormone receptor; LSHR: Lutropin-choriogonadotropic hormone receptor; FSHR: follicle stimulating hormone receptor. The scale bar indicates the number of changes per site. (GIF 41 KB)

427_2008_255_Fig8_ESM.eps (322 kb)
(EPS 330 KB)
427_2008_255_Fig9_ESM.gif (14 kb)
Fig. S9

Phylogenetic tree of TRH and related protein sequences. A maximum likelihood (ML) tree was obtained from analysis of TRH amino acid sequences. As no outgroup was found for TRH, the tree is presented unrooted. Bootstrap percentages obtained after 1,000 replicates are shown. The sequence from the chondrichthyes C. milii is indicated with a narrow green arrowhead. The amphioxus sequence is highlighted in red. TRH: Thyrotropin-releasing hormone. The scale bar indicates the number of changes per site (GIF 14 KB)

427_2008_255_Fig9_ESM.eps (395 kb)
(EPS 404 KB)

References

  1. Baqui M, Botero D, Gereben B, Curcio C, Harney JW, Salvatore D, Sorimachi K, Larsen PR, Bianco AC (2003) Human type 3 iodothyronine selenodeiodinase is located in the plasma membrane and undergoes rapid internalization to endosomes. J Biol Chem 278:1206–1211PubMedCrossRefGoogle Scholar
  2. Berry MJ, Banu L, Larsen PR (1991) Type I iodothyronine deiodinase is a selenocysteine-containing enzyme. Nature 349:438–440PubMedCrossRefGoogle Scholar
  3. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR (2002) Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89PubMedCrossRefGoogle Scholar
  4. Boorse GC, Denver RJ (2002) Acceleration of Ambystoma tigrinum metamorphosis by corticotropin-releasing hormone. J Exp Zool 293:94–98PubMedCrossRefGoogle Scholar
  5. Brusca RC, Brusca GJ (2003) Invertebrates. Sinauer Associates, SunderlandGoogle Scholar
  6. Callery EM, Fang H, Elinson RP (2001) Frogs without polliwogs: evolution of anuran direct development. Bioessays 23:233–241PubMedCrossRefGoogle Scholar
  7. Castresana J (2000) Selection of conserved blocks from multiple alignments for their use in phylogenetic analysis. Mol Biol Evol 17:540–552PubMedGoogle Scholar
  8. Covelli I, Salvatore G, Sena L, Roche J (1960) Sur la formation d’hormones thyroidiennes et de leurs précurseurs par Branchiostoma lanceolatum. C R Soc Biol Paris 154:1165–1169Google Scholar
  9. Curcio C, Baqui MM, Salvatore D, Rihn BH, Mohr S, Harney JW, Larsen PR, Bianco AC (2001) The human type 2 iodothyronine deiodinase is a selenoprotein highly expressed in a mesothelioma cell line. J Biol Chem 276:30183–30187PubMedCrossRefGoogle Scholar
  10. Daiyasu H, Toh H (2000) Molecular evolution of the myeloperoxidase family. J Mol Evol 51:433–445PubMedGoogle Scholar
  11. Dehal P, Boore JL (2005) Two rounds of whole genome duplication in the ancestral vertebrate. PLoS Biol 3:e314PubMedCrossRefGoogle Scholar
  12. Denver RJ (1997) Environmental stress as a developmental cue: corticotropin-releasing hormone is a proximate mediator of adaptive phenotypic plasticity in amphibian metamorphosis. Horm Behav 31:169–179PubMedCrossRefGoogle Scholar
  13. Dohan O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, Ginter CS, Carrasco N (2003) The sodium/iodide symporter (NIS): characterization, regulation, and medical significance. Endocr Rev 24:48–77PubMedCrossRefGoogle Scholar
  14. Eales JG (1997) Iodine metabolism and thyroid-related functions in organisms lacking thyroid follicles: are thyroid hormones also vitamins? Proc Soc Exp Biol Med 214:302–317PubMedGoogle Scholar
  15. Edgar RC (2004) MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32:1792–1797PubMedCrossRefGoogle Scholar
  16. Escriva H, Manzon L, Youson J, Laudet V (2002) Analysis of lamprey and hagfish genes reveals a complex history of gene duplications during early vertebrate evolution. Mol Biol Evol 19:1440–1450PubMedGoogle Scholar
  17. Flamant F, Samarut J (2003) Thyroid hormone receptors: lessons from knockout and knock-in mutant mice. Trends Endocrinol Metab 14:85–90PubMedCrossRefGoogle Scholar
  18. Flamant F, Baxter JD, Forrest D, Refetoff S, Samuels H, Scanlan TS, Vennstrom B, Samarut J (2006) International Union of Pharmacology. LIX. The pharmacology and classification of the nuclear receptor superfamily: thyroid hormone receptors. Pharmacol Rev 58:705–711PubMedCrossRefGoogle Scholar
  19. Force A, Lynch M, Pickett FB, Amores A, Yan YL, Postlethwait J (1999) Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151:1531–1545PubMedGoogle Scholar
  20. Fredriksson G, Öfverholm T, Ericson LE (1985) Electron-microscopic studies of iodine-binding and peroxidase activity in the endostyle of the larval amphioxus (Branchiostoma lanceolatum). Cell Tissue Res 241:257–266CrossRefGoogle Scholar
  21. Galtier N, Gouy M, Gautier C (1996) SEAVIEW and PHYLO_WIN: two graphic tools for sequence alignment and molecular phylogeny. Comput Appl Biosci 12:543–548PubMedGoogle Scholar
  22. Gopal E, Umapathy NS, Martin PM, Ananth S, Gnana-Prakasam JP, Becker H, Wagner CA, Ganapathy V, Prasad PD (2007) Cloning and functional characterization of human SMCT2 (SLC5A12) and expression pattern of the transporter in kidney. Biochim Biophys Acta 1768:2690–2697PubMedCrossRefGoogle Scholar
  23. Guindon S, Gascuel O (2003) A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. Syst Biol 52:696–704PubMedCrossRefGoogle Scholar
  24. Heyland A, Hodin J (2004) Heterochronic developmental shift caused by thyroid hormone in larval sand dollars and its implications for phenotypic plasticity and the evolution of nonfeeding development. Evolution Int J Org Evolution 58:524–538Google Scholar
  25. Heyland A, Reitzel AM, Price DA, Moroz LL (2006) Endogenous thyroid hormone synthesis in facultative planktotrophic larvae of the sand dollar Clypeaster rosaceus: implications for the evolutionary loss of larval feeding. Evol Dev 8:568–579PubMedCrossRefGoogle Scholar
  26. Hodin J (2006) Expanding networks: Signaling components in and a hypothesis for the evolution of metamorphosis. Integr Comp Biol 46:719–742CrossRefGoogle Scholar
  27. Holland LZ, Albalat R, Azumi K, Benito-Gutierrez E, Blow MJ, Bronner-Fraser M, Brunet F, Butts T, Candiani S, Dishaw LJ, Ferrier DE, Garcia-Fernandez J, Gibson-Brown JJ, Gissi C, Godzik A, Hallbook F, Hirose D, Hosomichi K, Ikuta T, Inoko H, Kasahara M, Kasamatsu J, Kawashima T, Kimura A, Kobayashi M, Kozmik Z, Kubokawa K, Laudet V, Litman GW, McHardy AC, Meulemans D, Nonaka M, Olinski RP, Pancer Z, Pennacchio LA, Pestarino M, Rast JP, Rigoutsos I, Robinson-Rechavi M, Roch G, Saiga H, Sasakura Y, Satake M, Satou Y, Schubert M, Sherwood N, Shiina T, Takatori N, Tello J, Vopalensky P, Wada S, Xu A, Ye Y, Yoshida K, Yoshizaki F, Yu JK, Zhang Q, Zmasek CM, de Jong PJ, Osoegawa K, Putnam NH, Rokhsar DS, Satoh N, Holland PW (2008) The amphioxus genome illuminates vertebrate origins and cephalochordate biology. Genome Res 18:1100–1111PubMedCrossRefGoogle Scholar
  28. Howard-Ashby M, Materna SC, Brown CT, Chen L, Cameron RA, Davidson EH (2006) Gene families encoding transcription factors expressed in early development of Strongylocentrotus purpuratus. Dev Biol 300:90–107PubMedCrossRefGoogle Scholar
  29. Hulbert AJ (2000) Thyroid hormones and their effects: a new perspective. Biol Rev Camb Philos Soc 75:519–631PubMedCrossRefGoogle Scholar
  30. Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigo R, Gladyshev VN (2003) Characterization of mammalian selenoproteomes. Science 300:1439–1443PubMedCrossRefGoogle Scholar
  31. Lynch M, Conery JS (2000) The evolutionary fate and consequences of duplicate genes. Science 290:1151–1155PubMedCrossRefGoogle Scholar
  32. Manzon RG, Holmes JA, Youson JH (2001) Variable effects of goitrogens in inducing precocious metamorphosis in sea lampreys (Petromyzon marinus). J Exp Zool 289:290–303PubMedCrossRefGoogle Scholar
  33. Manzon RG, Neuls TM, Manzon LA (2007) Molecular cloning, tissue distribution, and developmental expression of lamprey transthyretins. Gen Comp Endocrinol 151:55–65PubMedCrossRefGoogle Scholar
  34. Markov GV, Paris M, Bertrand S, Laudet V (2008) The evolution of the ligand/receptor couple: a long road from comparative endocrinology to comparative genomics. Mol Cell Endocrinol 293:5–16PubMedCrossRefGoogle Scholar
  35. Marletaz F, Gilles A, Caubit X, Perez Y, Dossat C, Samain S, Gyapay G, Wincker P, Le Parco Y (2008) Chaetognath transcriptome reveals ancestral and unique features among bilaterians. Genome Biol 9:R94PubMedCrossRefGoogle Scholar
  36. Monaco F, Dominici R, Andreoli M, Pirro RD, Roche J (1981) Thyroid hormone formation in thyroglobulin synthesized in the amphioxus (Branchiostoma lanceolatum Pallas). Comp Biochem Physiol B 70:341–343CrossRefGoogle Scholar
  37. Novinec M, Kordis D, Turk V, Lenarcic B (2006) Diversity and evolution of the thyroglobulin type-1 domain superfamily. Mol Biol Evol 23:744–755PubMedCrossRefGoogle Scholar
  38. Ogasawara M (2000) Overlapping expression of amphioxus homologs of the thyroid transcription factor-1 gene and thyroid peroxidase gene in the endostyle: insight into evolution of the thyroid gland. Dev Genes Evol 210:231–242PubMedCrossRefGoogle Scholar
  39. Ogasawara M, Di Lauro R, Satoh N (1999) Ascidian homologs of mammalian thyroid peroxidase genes are expressed in the thyroid-equivalent region of the endostyle. J Exp Zool 285:158–169PubMedCrossRefGoogle Scholar
  40. Ohno S (1970) Evolution by gene duplication. Springer, BerlinGoogle Scholar
  41. Paris M, Escriva H, Schubert M, Brunet F, Brtko J, Ciesielski F, Roecklin D, Vivat-Hannah V, Jamin EL, Cravedi JP, Scanlan TS, Renaud JP, Holland ND, Laudet V (2008) Amphioxus postembryonic development reveals the homology of chordate metamorphosis. Curr Biol 18:825–830PubMedCrossRefGoogle Scholar
  42. Paris M, Laudet V (2008) The history of developmental stages: metamorphosis in chordates. Genesis, in pressGoogle Scholar
  43. Patricolo E, Cammarata M, D'Agati P (2001) Presence of thyroid hormones in ascidian larvae and their involvement in metamorphosis. J Exp Zool 290:426–430PubMedCrossRefGoogle Scholar
  44. Power DM, Llewellyn L, Faustino M, Nowell MA, Bjornsson BT, Einarsdottir IE, Canario AV, Sweeney GE (2001) Thyroid hormones in growth and development of fish. Comp Biochem Physiol C Toxicol Pharmacol 130:447–459PubMedCrossRefGoogle Scholar
  45. Putnam NH, Butts T, Ferrier DE, Furlong RF, Hellsten U, Kawashima T, Robinson-Rechavi M, Shoguchi E, Terry A, Yu JK, Benito-Gutierrez EL, Dubchak I, Garcia-Fernandez J, Gibson-Brown JJ, Grigoriev IV, Horton AC, de Jong PJ, Jurka J, Kapitonov VV, Kohara Y, Kuroki Y, Lindquist E, Lucas S, Osoegawa K, Pennacchio LA, Salamov AA, Satou Y, Sauka-Spengler T, Schmutz J, Shin IT, Toyoda A, Bronner-Fraser M, Fujiyama A, Holland LZ, Holland PW, Satoh N, Rokhsar DS (2008) The amphioxus genome and the evolution of the chordate karyotype. Nature 453:1064–1071PubMedCrossRefGoogle Scholar
  46. Robinson M, Gouy M, Gautier C, Mouchiroud D (1998) Sensitivity of the relative-rate test to taxonomic sampling. Mol Biol Evol 15:1091–1098PubMedGoogle Scholar
  47. Rodriguez AM, Perron B, Lacroix L, Caillou B, Leblanc G, Schlumberger M, Bidart JM, Pourcher T (2002) Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes. J Clin Endocrinol Metab 87:3500–3503PubMedCrossRefGoogle Scholar
  48. Ruppert EE (2005) Key character uniting hemichordates and chordates: homologies or homoplasies. Can J Zool 83:8–23CrossRefGoogle Scholar
  49. Safi R, Bertrand S, Marchand O, Duffraisse M, de Luze A, Vanacker JM, Maraninchi M, Margotat A, Demeneix B, Laudet V (2004) The axolotl (Ambystoma mexicanum), a neotenic amphibian, expresses functional thyroid hormone receptors. Endocrinology 145:760–772PubMedCrossRefGoogle Scholar
  50. Schreiber G, Richardson SJ (1997) The evolution of gene expression, structure and function of transthyretin. Comp Biochem Physiol B Biochem Mol Biol 116:137–160PubMedCrossRefGoogle Scholar
  51. Schubert M, Brunet F, Paris M, Bertrand S, Benoit G, Laudet V (2008) Nuclear hormone receptor signaling in amphioxus. Dev Genes Evol, in pressGoogle Scholar
  52. Shepherdley CA, Klootwijk W, Makabe KW, Visser TJ, Kuiper GGJM (2004) An ascidian homolog of vertebrate iodothyronine deiodinases. Endocrinology 145:1255–1268PubMedCrossRefGoogle Scholar
  53. Shi Y-B (2000) Amphibian metamorphosis: from morphology to molecular biology. Wiley, New YorkGoogle Scholar
  54. Tata JR (2006) Amphibian metamorphosis as a model for the developmental actions of thyroid hormone. Mol Cell Endocrinol 246:10–20PubMedCrossRefGoogle Scholar
  55. Vandenborne K, Roelens SA, Darras VM, Kuhn ER, Van der Geyten S (2005) Cloning and hypothalamic distribution of the chicken thyrotropin-releasing hormone precursor cDNA. J Endocrinol 186:387–396PubMedCrossRefGoogle Scholar
  56. Wu SY, Green WL, Huang WS, Hays MT, Chopra IJ (2005) Alternate pathways of thyroid hormone metabolism. Thyroid 15:943–958PubMedCrossRefGoogle Scholar
  57. Yen PM (2001) Physiological and molecular basis of thyroid hormone action. Physiol Rev 81:1097–1142PubMedGoogle Scholar
  58. Youson JH (1997) Is lamprey metamorphosis regulated by thyroid hormones? Amer Zool 37:441–460Google Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Mathilde Paris
    • 1
  • Frédéric Brunet
    • 1
  • Gabriel V. Markov
    • 1
  • Michael Schubert
    • 1
  • Vincent Laudet
    • 1
  1. 1.Institut de Génomique Fonctionnelle de Lyon, CNRS UMR5242–INRA 1288–ENS–UCBL, IFR128 BioSciences Lyon-Gerland, Ecole Normale Supérieure de LyonLyon Cedex 07France

Personalised recommendations