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MEPE evolution in mammals reveals regions and residues of prime functional importance

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Abstract

In mammals, the matrix extracellular phosphoglycoprotein (MEPE) is known to activate osteogenesis and mineralization via a particular region called dentonin, and to inhibit mineralization via its ASARM (acidic serine-aspartate rich MEPE-associated motif) peptide that also plays a role in phosphatemia regulation. In order to understand MEPE evolution in mammals, and particularly that of its functional regions, we conducted an evolutionary analysis based on the study of selective pressures. Using 37 mammalian sequences we: (1) confirmed the presence of an additional coding exon in most placentals; (2) highlighted several conserved residues and regions that could have important functions; (3) found that dentonin function was recruited in a placental ancestor; and (4) revealed that ASARM function was present earlier, pushing the recruitment of MEPE deep into amniote origins. Our data indicate that MEPE was involved in various functions (bone and eggshell mineralization) prior to acquiring those currently known in placental mammals.

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References

  1. Rowe PS, de Zoysa PA, Dong R, Wang HR, White KE, Econs MJ, Oudet CL (2000) MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Genomics 67:54–68

    Article  CAS  PubMed  Google Scholar 

  2. Petersen DN, Tkalcevic GT, Mansolf AL, Rivera-Gonzalez R, Brown TA (2000) Identification of osteoblast/osteocyte factor 45 (OF45), a bone-specific cDNA encoding an RGD-containing protein that is highly expressed in osteoblasts and osteocytes. J Biol Chem 275:36172–36180

    Article  CAS  PubMed  Google Scholar 

  3. Gowen LC, Petersen DN, Mansolf AL, Qi H, Stock JL, Tkalcevic GT, Simmons HA, Crawford DT, Chidsey-Frink KL, Ke HZ, McNeish JD, Brown TA (2003) Targeted disruption of the osteoblast/osteocyte factor 45 gene (OF45) results in increased bone formation and bone mass. J Biol Chem 278:1998–2007

    Article  CAS  PubMed  Google Scholar 

  4. Fisher LW, Fedarko NS (2003) Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins. Connect Tissue Res 44:33–40

    CAS  PubMed  Google Scholar 

  5. Argiro L, Desbarats M, Glorieux FH, Ecarot B (2001) Mepe, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone. Genomics 74:342–351

    Article  CAS  PubMed  Google Scholar 

  6. Rowe PS (2004) The wrickkened pathways of FGF23, MEPE and PHEX. Crit Rev Oral Biol Med 15:264–281

    Article  PubMed  Google Scholar 

  7. Rowe PS, Kumagai Y, Gutierrez G, Garrett IR, Blacher R, Rosen D, Cundy J, Navvab S, Chen D, Drezner MK, Quarles LD, Mundy GR (2004) MEPE has the properties of an osteoblastic phosphatonin and minhibin. Bone 34:303–319

    Article  CAS  PubMed  Google Scholar 

  8. Addison WN, Nakano Y, Loisel T, Crine P, McKee MD (2008) MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. J Bone Miner Res 23:1638–1649

    Article  CAS  PubMed  Google Scholar 

  9. Guo R, Rowe PS, Liu S, Simpson LG, Xiao ZS, Quarles LD (2002) Inhibition of MEPE cleavage by Phex. Biochem Biophys Res Commun 297:38–45

    Article  CAS  PubMed  Google Scholar 

  10. Hayashibara T, Hiraga T, Yi B, Nomizu M, Kumagai Y, Nishimura R, Yoneda T (2004) A synthetic peptide fragment of human MEPE stimulates new bone formation in vitro and in vivo. J Bone Miner Res 19:455–462

    Article  CAS  PubMed  Google Scholar 

  11. Liu H, Li W, Gao C, Kumagai Y, Blacher RW, DenBesten PK (2004) Dentonin, a fragment of MEPE, enhanced dental pulp stem cell proliferation. J Dent Res 83:496–499

    Article  CAS  PubMed  Google Scholar 

  12. Goldberg M, Lacerda-Pinheiro S, Jegat N, Six N, Septier D, Priam F, Bonnefoix M, Tompkins K, Chardin H, Denbesten P, Veis A, Poliard A (2006) The impact of bioactive molecules to stimulate tooth repair and regeneration as part of restorative dentistry. Dent Clin North Am 50:277–298, x

    Google Scholar 

  13. Delgado S, Casane D, Bonnaud L, Laurin M, Sire JY, Girondot M (2001) Molecular evidence for precambrian origin of amelogenin, the major protein of vertebrate enamel. Mol Biol Evol 18:2146–2153

    CAS  PubMed  Google Scholar 

  14. Delgado S, Girondot M, Sire JY (2005) Molecular evolution of amelogenin in mammals. J Mol Evol 60:12–30

    Article  CAS  PubMed  Google Scholar 

  15. Delgado S, Couble ML, Magloire H, Sire JY (2006) Cloning, sequencing, and expression of the amelogenin gene in two scincid lizards. J Dent Res 85:138–143

    Article  CAS  PubMed  Google Scholar 

  16. Sire JY, Delgado S, Girondot M (2006) The amelogenin story: origin and evolution. Eur J Oral Sci 114(Suppl 1):64–77

    Article  CAS  PubMed  Google Scholar 

  17. Subramanian S, Kumar S (2006) Evolutionary anatomies of positions and types of disease-associated and neutral amino acid mutations in the human genome. BMC Genomics 7:306

    Article  PubMed  Google Scholar 

  18. Delgado S, Ishiyama M, Sire JY (2007) Validation of amelogenesis imperfecta inferred from amelogenin evolution. J Dent Res 86:326–330

    Article  CAS  PubMed  Google Scholar 

  19. Springer MS, Murphy WJ (2007) Mammalian evolution and biomedicine: new views from phylogeny. Biol Rev Camb Philos Soc 82:375–392

    Article  PubMed  Google Scholar 

  20. Rambaut A (1996) Se-Al sequence alignment editor. Zoology Department, University of Oxford, Oxford

  21. Kosakovsky Pond SL, Frost SD, Muse SV (2005) HyPhy: hypothesis testing using phylogenies. Bioinformatics 21:676–679

    Article  Google Scholar 

  22. Maddison DR, Maddison WP (2005) MacClade4 Version 4.08. Sinauer, Sunderland, Mass.

  23. Doron-Faigenboim A, Stern A, Mayrose I, Bacharach E, Pupko T (2005) Selecton: a server for detecting evolutionary forces at a single amino-acid site. Bioinformatics 21:2101–2103

    Article  CAS  PubMed  Google Scholar 

  24. Stern A, Doron-Faigenboim A, Erez E, Martz E, Bacharach E, Pupko T (2007) Selecton 2007: advanced models for detecting positive and purifying selection using a Bayesian inference approach. Nucleic Acids Res 35:506–511

    Article  Google Scholar 

  25. Tsunoyama K, Gojobori T (1998) Evolution of nicotinic acetylcholine receptor subunits. Mol Biol Evol 15:518–527

    CAS  PubMed  Google Scholar 

  26. Hasegawa M, Kishino H, Yano T (1985) Dating of the human-ape splitting by a molecular clock of mitochondrial DNA. J Mol Evol 22:160–174

    Article  CAS  PubMed  Google Scholar 

  27. Kosakovsky Pond SL, Frost SD (2005) Datamonkey: rapid detection of selective pressure on individual sites of codon alignments. Bioinformatics 21:2531–2533

    Article  Google Scholar 

  28. Kosakovsky Pond SL, Frost SD (2005) Not so different after all: a comparison of methods for detecting amino acid sites under selection. Mol Biol Evol 22:1208–1222

    Article  PubMed  Google Scholar 

  29. Tamura K, Nei M (1993) Estimation of the number of nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzees. Mol Biol Evol 10:512–526

    CAS  PubMed  Google Scholar 

  30. Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4:406–425

    CAS  PubMed  Google Scholar 

  31. Murphy WJ, Pringle TH, Crider TA, Springer MS, Miller W (2007) Using genomic data to unravel the root of the placental mammal phylogeny. Genome Res 17:413–421

    Article  CAS  PubMed  Google Scholar 

  32. Hincke MT, Gautron J, Tsang CP, McKee MD, Nys Y (1999) Molecular cloning and ultrastructural localization of the core protein of an eggshell matrix proteoglycan, ovocleidin-116. J Biol Chem 274:32915–32923

    Article  CAS  PubMed  Google Scholar 

  33. Consortium ICS (2004) Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432:695–716

    Article  Google Scholar 

  34. Kawasaki K, Weiss KM (2006) Evolutionary genetics of vertebrate tissue mineralization: the origin and evolution of the secretory calcium-binding phosphoprotein family. J Exp Zool B Mol Dev Evol 306:295–316

    Article  PubMed  Google Scholar 

  35. Horvat-Gordon M, Yu F, Burns D, Leach RM Jr (2008) Ovocleidin (OC 116) is present in avian skeletal tissues. Poult Sci 87:1618–1623

    Article  CAS  PubMed  Google Scholar 

  36. Warren WC, Hillier LW, Marshall Graves JA, Birney E, Ponting CP, Grutzner F, Belov K, Miller W, Clarke L, Chinwalla AT, Yang SP, Heger A, Locke DP, Miethke P, Waters PD, Veyrunes F, Fulton L, Fulton B, Graves T, Wallis J, Puente XS, López-Otín C, Ordóñez GR, Eichler EE, Chen L, Cheng Z, Deakin JE, Alsop A, Thompson K, Kirby P, Papenfuss AT, Wakefield MJ, Olender T, Lancet D, Huttley GA, Smit AF, Pask A, Temple-Smith P, Batzer MA, Walker JA, Konkel MK, Harris RS, Whittington CM, Wong ES, Gemmell NJ, Buschiazzo E, Vargas Jentzsch IM, Merkel A, Schmitz J, Zemann A, Churakov G, Kriegs JO, Brosius J, Murchison EP, Sachidanandam R, Smith C, Hannon GJ, Tsend-Ayush E, McMillan D, Attenborough R, Rens W, Ferguson-Smith M, Lefèvre CM, Sharp JA, Nicholas KR, Ray DA, Kube M, Reinhardt R, Pringle TH, Taylor J, Jones RC, Nixon B, Dacheux JL, Niwa H, Sekita Y, Huang X, Stark A, Kheradpour P, Kellis M, Flicek P, Chen Y, Webber C, Hardison R, Nelson J, Hallsworth-Pepin K, Delehaunty K, Markovic C, Minx P, Feng Y, Kremitzki C, Mitreva M, Glasscock J, Wylie T, Wohldmann P, Thiru P, Nhan MN, Pohl CS, Smith SM, Hou S, Nefedov M, de Jong PJ, Renfree MB, Mardis ER, Wilson RK (2008) Genome analysis of the platypus reveals unique signatures of evolution. Nature 453:175–183

    Article  CAS  PubMed  Google Scholar 

  37. Hughes RL, Carrick FN (1978) Reproduction in female monotremes. Aust Zool 20:233–253

    Google Scholar 

  38. Palmer BD, Guillette LJ (2004) Oviductal proteins and their influence on embryonic development in birds and reptiles. In: Deeming DC, Ferguson MWJ (eds) Egg incubation: its effects on embryonic development in birds and reptiles. Cambridge University Press, Cambridge, pp 29–46

    Google Scholar 

  39. Kawasaki K (2009) The SCPP gene repertoire in bony vertebrates and graded differences in mineralized tissues. Dev Genes Evol 219:147–157

    Article  CAS  PubMed  Google Scholar 

  40. Osada N, Hida M, Kusuda J, Tanuma R, Iseki K, Hirai M, Terao K, Suzuki Y, Sugano S, Hashimoto K (2000) Isolation of full-length cDNA clones from macaque brain cDNA libraries. [http://www.ncbi.nlm.nih.gov/nuccore/13874559]

  41. Kawasaki K, Weiss KM (2003) Mineralized tissue and vertebrate evolution: the secretory calcium-binding phosphoprotein gene cluster. Proc Natl Acad Sci USA 100:4060–4065

    Article  CAS  PubMed  Google Scholar 

  42. Shintani S, Kamakura N, Kobata M, Toyosawa S, Onishi T, Sato A, Kawasaki K, Weiss KM, Ooshima T (2008) Identification and characterization of integrin-binding sialoprotein (IBSP) genes in reptile and amphibian. Gene 424:11–17

    Article  CAS  PubMed  Google Scholar 

  43. Yang R, Gerstenfeld LC (1997) Structural analysis and characterization of tissue and hormonal responsive expression of the avian bone sialoprotein (BSP) gene. J Cell Biochem 64:77–93

    Article  CAS  PubMed  Google Scholar 

  44. Tompa P (2002) Intrinsically unstructured proteins. Trends Biochem Sci 27:527–533

    Article  CAS  PubMed  Google Scholar 

  45. Chen JW, Romero P, Uversky VN, Dunker AK (2006) Conservation of intrinsic disorder in protein domains and families: II. functions of conserved disorder. J Proteome Res 5:888–898

    Article  PubMed  Google Scholar 

  46. Mann K, Hincke MT, Nys Y (2002) Isolation of ovocleidin-116 from chicken eggshells, correction of its amino acid sequence and identification of disulfide bonds and glycosylated Asn. Matrix Biol 21:383–387

    Article  CAS  PubMed  Google Scholar 

  47. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456:470–476

    Article  CAS  PubMed  Google Scholar 

  48. Veis A (2003) Amelogenin gene splice products: potential signaling molecules. Cell Mol Life Sci 60:38–55

    Article  CAS  PubMed  Google Scholar 

  49. Narayanan K, Gajjeraman S, Ramachandran A, Hao J, George A (2006) Dentin matrix protein 1 regulates dentin sialophosphoprotein gene transcription during early odontoblast differentiation. J Biol Chem 281:19064–19071

    Article  CAS  PubMed  Google Scholar 

  50. Dunker AK, Oldfield CJ, Meng J, Romero P, Yang JY, Chen JW, Vacic V, Obradovic Z, Uversky VN (2008) The unfoldomics decade: an update on intrinsically disordered proteins. BMC Genomics 9:S1

    Article  Google Scholar 

  51. Dee KC, Andersen TT, Bizios R (1998) Design and function of novel osteoblast-adhesive peptides for chemical modification of biomaterials. J Biomed Mater Res 40:371–377

    Article  CAS  PubMed  Google Scholar 

  52. Martin A, David V, Laurence JS, Schwarz PM, Lafer EM, Hedge AM, Rowe PS (2008) Degradation of MEPE, DMP1 and release of SIBLING ASARM-peptides (minhibins): ASARM-peptide(s) are directly responsible for defective mineralization in HYP. Endocrinology 149:1757–1772

    Article  CAS  PubMed  Google Scholar 

  53. Kasugai S, Zhang Q, Overall CM, Wrana JL, Butler WT, Sodek J (1991) Differential regulation of the 55 and 44 kDa forms of secreted phosphoprotein 1 (SPP-1, osteopontin) in normal and transformed rat bone cells by osteotropic hormones, growth factors and a tumor promoter. Bone Miner 13:235–250

    Article  CAS  PubMed  Google Scholar 

  54. Christensen B, Kazanecki CC, Petersen TE, Rittling SR, Denhardt DT, Sorensen ES (2007) Cell type-specific post-translational modifications of mouse osteopontin are associated with different adhesive properties. J Biol Chem 282:19463–19472

    Article  CAS  PubMed  Google Scholar 

  55. Boskey AL (1995) Osteopontin and related phosphorylated sialoproteins: effects on mineralization. Ann N Y Acad Sci 760:249–256

    Article  CAS  PubMed  Google Scholar 

  56. Ek-Rylander B, Flores M, Wendel M, Heinegard D, Andersson G (1994) Dephosphorylation of osteopontin and bone sialoprotein by osteoclastic tartrate-resistant acid phosphatase. Modulation of osteoclast adhesion in vitro. J Biol Chem 269:14853–14856

    CAS  PubMed  Google Scholar 

  57. Al-Shami R, Sorensen ES, Ek-Rylander B, Andersson G, Carson DD, Farach-Carson MC (2005) Phosphorylated osteopontin promotes migration of human choriocarcinoma cells via a p70 S6 kinase-dependent pathway. J Cell Biochem 94:1218–1233

    Article  CAS  PubMed  Google Scholar 

  58. Bresler D, Bruder J, Mohnike K, Fraser WD, Rowe PS (2004) Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets. J Endocrinol 183:R1–R9

    Article  CAS  PubMed  Google Scholar 

  59. Suzuki Y, Gojobori T (1999) A Method for detecting positive selection at single amino acid sites. Mol Biol Evol 16:1315–1328

    CAS  PubMed  Google Scholar 

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Acknowledgments

We express our sincere thanks to IFRO (Institut Français pour la Recherche Odontologique) for financial support to CB and to Dr Matthew Vickarious (Ontario Veterinary College, University of Guelph, Canada) for English corrections. We also are grateful to Professor Jorge Cubo (UPMC) for his help in performing statistical analyses and to Dr Guillaume Achaz (UPMC) for helpful discussion. This work was supported by CNRS and UPMC (UMR 7138) grants.

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Authors and Affiliations

  1. UMR 7138, Equipe “Evolution & Développement du Squelette” Université Paris 6, Paris, France

    Claire Bardet, Sidney Delgado & Jean-Yves Sire

  2. UMR 7138, Université Pierre et Marie Curie-Paris 6, Case 05, 7 Quai St-Bernard, 75005, Paris, France

    Jean-Yves Sire

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  1. Claire Bardet
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  2. Sidney Delgado
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Correspondence to Jean-Yves Sire.

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18_2009_185_MOESM1_ESM.pdf

Alignment of the 37 amino acid sequences of mammalian MEPE. The human sequence was used as a reference sequence for this alignment, which takes into consideration mammalian relationships (see Fig. 1). Note that exon 3 and/or exon 4 are invalidated in some species. The 23 amino acid-long dentonin region (synthetical peptide AC-100) is located in the central region encoded by exon 5. It contains two important motifs, RGD and SGDG (boxed), which are preserved in most species. However, RGD is absent in several sequences and the two motifs are missing in marsupials. The amino acids of the ASARM peptide (Cterminus, boxed) are well conserved in all sequences studied, but in the two marsupials the ASARM sequence is followed by a dozen of residues. Newly identified important motifs are boxed in gray background. [ ] exon limits; (.) residue identical to human sequence; (-) Indel; (=) Unknown residue; (#) Residue identical in all sequences; (+) Residue identical in all therian sequences. (PDF 111 kb)

18_2009_185_MOESM2_ESM.jpg

Tree distance obtained using the distance matrix of the 37 mammalian MEPE. The relationships between species do not refelct current mammalian phylogeny (compare with Fig. 1). The species in which MEPE shows a high rate of evolution are artefactually attracted to the base of the tree (e.g., rodents and insectivores). (JPG 450 kb)

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Bardet, C., Delgado, S. & Sire, JY. MEPE evolution in mammals reveals regions and residues of prime functional importance. Cell. Mol. Life Sci. 67, 305–320 (2010). https://doi.org/10.1007/s00018-009-0185-1

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