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Differential expression of the bone and the liver tissue non-specific alkaline phosphatase isoforms in brain tissues

Abstract

The enzyme tissue non-specific alkaline phosphatase (TNAP) belongs to the ectophosphatase family. It is present in large amounts in bone in which it plays a role in mineralization but little is known about its function in other tissues. Arguments are accumulating for its involvement in the brain, in particular in view of the neurological symptoms accompanying human TNAP deficiencies. We have previously shown, by histochemistry, alkaline phosphatase (AP) activity in monkey brain vessels and parenchyma in which AP exhibits specific patterns. Here, we clearly attribute this activity to TNAP expression rather than to other APs in primates (human and marmoset) and in rodents (rat and mouse). We have not found any brain-specific transcripts but our data demonstrate that neuronal and endothelial cells exclusively express the bone TNAP transcript in all species tested, except in mouse neurons in which liver TNAP transcripts have also been detected. Moreover, we highlight the developmental regulation of TNAP expression; this also acts during neuronal differentiation. Our study should help to characterize the regulation of the expression of this ectophosphatase in various cell types of the central nervous system.

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References

  1. Anstrom JA, Brown WR, Moody DM, Thore CR, Challa VR, Block SM (2002) Temporal expression pattern of cerebrovascular endothelial cell alkaline phosphatase during human gestation. J Neuropathol Exp Neurol 61:76–84

  2. Anstrom JA, Thore CR, Moody DM, Brown WR (2007) Immunolocalization of tight junction proteins in blood vessels in human germinal matrix and cortex. Histochem Cell Biol 127:205–213

  3. Balasubramaniam S, Bowling F, Carpenter K, Earl J, Chaitow J, Pitt J, Mornet E, Sillence D, Ellaway C (2010) Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5′-phosphate availability. J Inherit Metab Dis. Epub ahead of print

  4. Bell MA, Ball MJ (1985) Laminar variation in the microvascular architecture of normal human visual cortex (area 17). Brain Res 335:139–143

  5. Brun-Heath I, Taillandier A, Serre JL, Mornet E (2005) Characterization of 11 novel mutations in the tissue non-specific alkaline phosphatase gene responsible for hypophosphatasia and genotype-phenotype correlations. Mol Genet Metab 84:273–277

  6. Calhau C, Martel F, Pinheiro-Silva S, Pinheiro H, Soares-da-Silva P, Hipolito-Reis C, Azevedo I (2002) Modulation of insulin transport in rat brain microvessel endothelial cells by an ecto-phosphatase activity. J Cell Biochem 84:389–400

  7. Coisne C, Dehouck L, Faveeuw C, Delplace Y, Miller F, Landry C, Morissette C, Fenart L, Cecchelli R, Tremblay P, Dehouck B (2005) Mouse syngenic in vitro blood-brain barrier model: a new tool to examine inflammatory events in cerebral endothelium. Lab Invest 85:734–746

  8. Diaz-Hernandez M, Gomez-Ramos A, Rubio A, Gomez-Villafuertes R, Naranjo J, Miras-Portugal M, Avila J (2010) Tissue non-specific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. J Biol Chem 285:32539–32548

  9. Ehrlich YH, Davis TB, Bock E, Kornecki E, Lenox RH (1986) Ecto-protein kinase activity on the external surface of neural cells. Nature 320:67–70

  10. el-Moatassim C, Dornand J, Mani JC (1992) Extracellular ATP and cell signalling. Biochim Biophys Acta 1134:31–45

  11. Ermonval M, Baudry A, Baychelier F, Pradines E, Pietri M, Oda K, Schneider B, Mouillet-Richard S, Launay JM, Kellermann O (2009) The cellular prion protein interacts with the tissue non-specific alkaline phosphatase in membrane microdomains of bioaminergic neuronal cells. PLoS ONE 4:e6497

  12. Escalante-Alcalde D, Recillas-Targa F, Hernandez-Garcia D, Castro-Obregon S, Terao M, Garattini E, Covarrubias L (1996) Retinoic acid and methylation cis-regulatory elements control the mouse tissue non-specific alkaline phosphatase gene expression. Mech Dev 57:21–32

  13. Fonta C, Imbert M (2002) Vascularization in the primate visual cortex during development. Cereb Cortex 12:199–211

  14. Fonta C, Negyessy L, Renaud L, Barone P (2004) Areal and subcellular localization of the ubiquitous alkaline phosphatase in the primate cerebral cortex: evidence for a role in neurotransmission. Cereb Cortex 14:595–609

  15. Fonta C, Negyessy L, Renaud L, Barone P (2005) Postnatal development of alkaline phosphatase activity correlates with the maturation of neurotransmission in the cerebral cortex. J Comp Neurol 486:179–196

  16. Halling Linder C, Narisawa S, Millan JL, Magnusson P (2009) Glycosylation differences contribute to distinct catalytic properties among bone alkaline phosphatase isoforms. Bone 45:987–993

  17. Heath JK, Suva LJ, Yoon K, Kiledjian M, Martin TJ, Rodan GA (1992) Retinoic acid stimulates transcriptional activity from the alkaline phosphatase promoter in the immortalized rat calvarial cell line, RCT-1. Mol Endocrinol 6:636–646

  18. Henthorn PS, Raducha M, Fedde KN, Lafferty MA, Whyte MP (1992) Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia. Proc Natl Acad Sci USA 89:9924–9928

  19. Hessle L, Johnson KA, Anderson HC, Narisawa S, Sali A, Goding JW, Terkeltaub R, Millan JL (2002) Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proc Natl Acad Sci USA 99:9445–9449

  20. Johnson-Pais TL, Leach RJ (1996) 1,25-Dihydroxyvitamin D3 and transforming growth factor-beta act synergistically to override extinction of liver/bone/kidney alkaline phosphatase in osteosarcoma hybrid cells. Exp Cell Res 226:67–74

  21. Kiledjian M, Kadesch T (1991) Post-transcriptional regulation of the human liver/bone/kidney alkaline phosphatase gene. J Biol Chem 266:4207–4213

  22. Kruse K, Hanefeld F, Kohlschutter A, Rosskamp R, Gross-Selbeck G (1988) Hyperphosphatasia with mental retardation. J Pediatr 112:436–439

  23. Kyeyune-Nyombi E, Lau KH, Baylink DJ, Strong DD (1991) 1,25-Dihydroxyvitamin D3 stimulates both alkaline phosphatase gene transcription and mRNA stability in human bone cells. Arch Biochem Biophys 291:316–325

  24. Langer D, Ikehara Y, Takebayashi H, Hawkes R, Zimmermann H (2007) The ectonucleotidases alkaline phosphatase and nucleoside triphosphate diphosphohydrolase 2 are associated with subsets of progenitor cell populations in the mouse embryonic, postnatal and adult neurogenic zones. Neuroscience 150:863–879

  25. Langer D, Hammer K, Koszalka P, Schrader J, Robson S, Zimmermann H (2008) Distribution of ectonucleotidases in the rodent brain revisited. Cell Tissue Res 334:199–217

  26. Lyck R, Ruderisch N, Moll AG, Steiner O, Cohen CD, Engelhardt B, Makrides V, Verrey F (2009) Culture-induced changes in blood-brain barrier transcriptome: implications for amino-acid transporters in vivo. J Cereb Blood Flow Metab 29:1491–1502

  27. Mabry CC, Bautista A, Kirk RF, Dubilier LD, Braunstein H, Koepke JA (1970) Familial hyperphosphatase with mental retardation, seizures, and neurologic deficits. J Pediatr 77:74–85

  28. Martin DL, Martin SB, Wu SJ, Espina N (1991) Regulatory properties of brain glutamate decarboxylase (GAD): the apoenzyme of GAD is present principally as the smaller of two molecular forms of GAD in brain. J Neurosci 11:2725–2731

  29. Matsuura S, Kishi F, Kajii T (1990) Characterization of a 5′-flanking region of the human liver/bone/kidney alkaline phosphatase gene: two kinds of mRNA from a single gene. Biochem Biophys Res Commun 168:993–1000

  30. Mayahara H, Hirano H, Saito T, Ogawa K (1967) The new lead citrate method for the ultracytochemical demonstration of activity of non-specific alkaline phosphatase (orthophosphoric monoester phosphohydrolase). Histochemie 11:88–96

  31. Millan JL (2006) Mammalian alkaline phosphatases. From biology to applications in medicine and biotechnology. Wiley-VCH, Weinheim

  32. Moody DM, Thore CR, Anstrom JA, Challa VR, Langefeld CD, Brown WR (2004) Quantification of afferent vessels shows reduced brain vascular density in subjects with leukoaraiosis. Radiology 233:883–890

  33. Mori S, Nagano M (1985) Electron microscopic cytochemistry of alkaline phosphatase in neurons of rats. Arch Histol Jpn 48:389–397

  34. Mornet E (2008) Hypophosphatasia. Best Pract Res Clin Rheumatol 22:113–127

  35. Mornet E, Stura E, Lia-Baldini AS, Stigbrand T, Menez A, Le Du MH (2001) Structural evidence for a functional role of human tissue nonspecific alkaline phosphatase in bone mineralization. J Biol Chem 276:31171–31178

  36. Mouillet-Richard S, Mutel V, Loric S, Tournois C, Launay JM, Kellermann O (2000) Regulation by neurotransmitter receptors of serotonergic or catecholaminergic neuronal cell differentiation. J Biol Chem 275:9186–9192

  37. Mueller WH, Kleefeld D, Khattab B, Meissner JD, Scheibe RJ (2000) Effects of retinoic acid on N-glycosylation and mRNA stability of the liver/bone/kidney alkaline phosphatase in neuronal cells. J Cell Physiol 182:50–61

  38. Nakazato H, Deguchi M, Fujimoto M, Fukushima H (1997) Alkaline phosphatase expression in cultured endothelial cells of aorta and brain microvessels: induction by interleukin-6-type cytokines and suppression by transforming growth factor betas. Life Sci 61:2065–2072

  39. Narisawa S, Hasegawa H, Watanabe K, Millan JL (1994) Stage-specific expression of alkaline phosphatase during neural development in the mouse. Dev Dyn 201:227–235

  40. Narisawa S, Frohlander N, Millan JL (1997) Inactivation of two mouse alkaline phosphatase genes and establishment of a model of infantile hypophosphatasia. Dev Dyn 208:432–446

  41. Neary JT, Zimmermann H (2009) Trophic functions of nucleotides in the central nervous system. Trends Neurosci 32:189–198

  42. Negyessy L, Xiao J, Kantor O, Kovacs GG, Palkovits M, Doczi TP, Renaud L, Baksa G, Glasz T, Ashaber M, Barone P, Fonta C (2010) Layer-specific activity of tissue non-specific alkaline phosphatase in the human neocortex. Neuroscience. Epub ahead of print

  43. Nouwen EJ, De Broe ME (1994) Human intestinal versus tissue-nonspecific alkaline phosphatase as complementary urinary markers for the proximal tubule. Kidney Int Suppl 47:S43–S51

  44. Orimo H, Shimada T (2005) Regulation of the human tissue-nonspecific alkaline phosphatase gene expression by all-trans-retinoic acid in SaOS-2 osteosarcoma cell line. Bone 36:866–876

  45. Ovtscharoff W (1973) Ultracytochemical localisation of the alkaline phosphatase in the cerebral cortex of newborn rats. Histochemie 37:93–95

  46. Plesner L (1995) Ecto-ATPases: identities and functions. Int Rev Cytol 158:141–214

  47. Rathbun JC (1948) Hypophosphatasia; a new developmental anomaly. Am J Dis Child 75:822–831

  48. Risau W, Hallmann R, Albrecht U, Henke-Fahle S (1986) Brain induces the expression of an early cell surface marker for blood-brain barrier-specific endothelium. EMBO J 5:3179–3183

  49. Robson SC, Sevigny J, Zimmermann H (2006) The E-NTPDase family of ectonucleotidases: structure function relationships and pathophysiological significance. Purinergic Signal 2:409–430

  50. San Miguel SM, Goseki-Sone M, Sugiyama E, Watanabe H, Yanagishita M, Ishikawa I (1999) Tissue-non-specific alkaline phosphatase mRNA expression and alkaline phosphatase activity following application of retinoic acid in cultured human dental pulp cells. Arch Oral Biol 44:861–869

  51. Scheibe RJ, Ginty DD, Wagner JA (1991) Retinoic acid stimulates the differentiation of PC12 cells that are deficient in cAMP-dependent protein kinase. J Cell Biol 113:1173–1182

  52. Scherer SS (1996) Molecular specializations at nodes and paranodes in peripheral nerve. Microsc Res Tech 34:452–461

  53. Schmidt F, Champy P, Seon-Meniel B, Franck X, Raisman-Vozari R, Figadere B (2009) Chemicals possessing a neurotrophin-like activity on dopaminergic neurons in primary culture. PLoS ONE 4:e6215

  54. Schneider BF, Norton S (1979) Equivalent ages in rat, mouse and chick embryos. Teratology 19:273–278

  55. Smith D, Wagner E, Koul O, McCaffery P, Drager UC (2001) Retinoic acid synthesis for the developing telencephalon. Cereb Cortex 11:894–905

  56. Sobue K, Yamamoto N, Yoneda K, Hodgson ME, Yamashiro K, Tsuruoka N, Tsuda T, Katsuya H, Miura Y, Asai K, Kato T (1999) Induction of blood-brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci Res 35:155–164

  57. Stephens MC, Dakshinamurti K (1975) Brain lipids in pyridoxine-deficient young rats. Neurobiology 5:262–269

  58. Studer M, Terao M, Gianni M, Garattini E (1991) Characterization of a second promoter for the mouse liver/bone/kidney-type alkaline phosphatase gene: cell and tissue specific expression. Biochem Biophys Res Commun 179:1352–1360

  59. Takemoto H, Kaneda K, Hosokawa M, Ide M, Fukushima H (1994) Conditioned media of glial cell lines induce alkaline phosphatase activity in cultured artery endothelial cells. Identification of interleukin-6 as an induction factor. FEBS Lett 350:99–103

  60. Tam PP, Kwong WH (1987) A study on the pattern of alkaline phosphatase activity correlated with observations on silver-impregnated structures in the developing mouse brain. J Anat 150:169–180

  61. Taniura H, Ito M, Sanada N, Kuramoto N, Ohno Y, Nakamichi N, Yoneda Y (2006) Chronic vitamin D3 treatment protects against neurotoxicity by glutamate in association with upregulation of vitamin D receptor mRNA expression in cultured rat cortical neurons. J Neurosci Res 83:1179–1189

  62. Thompson MD, Nezarati MM, Gillessen-Kaesbach G, Meinecke P, Mendoza R, Mornet E, Brun-Heath I, Squarcioni CP, Legeai-Mallet L, Munnich A, Cole DE (2010) Hyperphosphatasia with seizures, neurologic deficit, and characteristic facial features: five new patients with Mabry syndrome. Am J Med Genet A 152A:1661–1669

  63. Toh Y, Yamamoto M, Endo H, Misumi Y, Ikehara Y (1989) Isolation and characterization of a rat liver alkaline phosphatase gene. A single gene with two promoters. Eur J Biochem 182:231–237

  64. Van Belle H (1976) Alkaline phosphatase. I. Kinetics and inhibition by levamisole of purified isoenzymes from humans. Clin Chem 22:972–976

  65. Waymire KG, Mahuren JD, Jaje JM, Guilarte TR, Coburn SP, MacGregor GR (1995) Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6. Nat Genet 11:45–51

  66. Weiss MJ, Ray K, Henthorn PS, Lamb B, Kadesch T, Harris H (1988) Structure of the human liver/bone/kidney alkaline phosphatase gene. J Biol Chem 263:12002–12010

  67. Weksler BB, Subileau EA, Perriere N, Charneau P, Holloway K, Leveque M, Tricoire-Leignel H, Nicotra A, Bourdoulous S, Turowski P, Male DK, Roux F, Greenwood J, Romero IA, Couraud PO (2005) Blood-brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J 19:1872–1874

  68. Wennberg C, Hessle L, Lundberg P, Mauro S, Narisawa S, Lerner UH, Millan JL (2000) Functional characterization of osteoblasts and osteoclasts from alkaline phosphatase knockout mice. J Bone Miner Res 15:1879–1888

  69. Whyte MP (1994) Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocr Rev 15:439–461

  70. Whyte MP, Mahuren JD, Vrabel LA, Coburn SP (1985) Markedly increased circulating pyridoxal-5′-phosphate levels in hypophosphatasia. Alkaline phosphatase acts in vitamin B6 metabolism. J Clin Invest 76:752–756

  71. Yusa N, Watanabe K, Yoshida S, Shirafuji N, Shimomura S, Tani K, Asano S, Sato N (2000) Transcription factor Sp3 activates the liver/bone/kidney-type alkaline phosphatase promoter in hematopoietic cells. J Leukoc Biol 68:772–777

  72. Zernik J, Kream B, Twarog K (1991) Tissue-specific and dexamethasone-inducible expression of alkaline phosphatase from alternative promoters of the rat bone/liver/kidney/placenta gene. Biochem Biophys Res Commun 176:1149–1156

  73. Zimmermann H (2006) Nucleotide signaling in nervous system development. Pflugers Arch 452:573–588

  74. Zoellner HF, Hunter N (1989) Histochemical identification of the vascular endothelial isoenzyme of alkaline phosphatase. J Histochem Cytochem 37:1893–1898

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Acknowledgements

We thank Dr. Lászlo Négyessi (Semmelweiss University, Budapest, Hungary) and Gabor G. Kovacs (former National Institute of Psychiatry and Neurology, Budapest, Hungary) for support and advice and for providing human samples. We are grateful to Prof. Jean Sautet for his valuable expertise in embryonic anatomy. We thank Luc Renaud for the histology work. We acknowledge Prof. Odile Kellermann and Prof. Jean-Marie Launay for material derived from the 1C11 neuronal model. We are also grateful to Simon Heath for careful reading of the manuscript.

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Correspondence to Caroline Fonta.

Additional information

This study was supported by PHC Egide (Balaton 17341UE), CNRS (PICS 4331), Hypophosphatasie Europe, the University of Toulouse (ASUPS and ATUPS) and the French Embassy in Beijing.

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Fig. S1

Alignment of ALPL exon 1A including the 2-kb upstream sequence from five primate species; the 2142 bp including ALPL exon 1A (bold) and the 2050-bp upstream sequence from human were aligned with homologous sequences from chimpanzee, orangutan, macaque rhesus and marmoset. Note that 200-250 bp are missing from the orangutan sequence because of the incomplete sequencing in this species. Predicted or validated regulatory elements are highlighted: yellow vitamin-D-regulating elements (Matinspector prevision software, this study), green TATA box (Orimo and Shimada 2005), grey Sp1/Sp3-binding sites (Orimo and Shimada 2005; Yusa et al. 2000), turquoise sequence resembling retinoic-acid-responsive element (DR2 motif; Orimo and Shimada 2005). The arrow indicates the major transcription start site (position 2050 in the human sequence) (PDF 38 kb)

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Brun-Heath, I., Ermonval, M., Chabrol, E. et al. Differential expression of the bone and the liver tissue non-specific alkaline phosphatase isoforms in brain tissues. Cell Tissue Res 343, 521–536 (2011). https://doi.org/10.1007/s00441-010-1111-4

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Keywords

  • Ectophosphatase
  • Cerebral endothelial cell
  • Neuron
  • Primate
  • Rodent