Skip to main content
Springer Nature Link
Log in

Development of the blood-brain barrier

  • Review Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

The endothelial cells forming the blood-brain barrier (BBB) are highly specialized to allow precise control over the substances that leave or enter the brain. An elaborate network of complex tight junctions (TJ) between the endothelial cells forms the structural basis of the BBB and restricts the paracellular diffusion of hydrophilic molecules. Additonally, the lack of fenestrae and the extremely low pinocytotic activity of endothelial cells of the BBB inhibit the transcellular passage of molecules across the barrier. On the other hand, in order to meet the high metabolic needs of the tissue of the central nervous system (CNS), specific transport systems selectively expressed in the membranes of brain endothelial cells in capillaries mediate the directed transport of nutrients into the CNS or of toxic metabolites out of the CNS. Whereas the characteristics of the mature BBB endothelium are well described, the cellular and molecular mechanisms that control the development, differentiation and maintenance of the highly specialized endothelial cells of the BBB remain unknown to date, despite the recent explosion in our knowledge of the growth factors and their receptors specifically acting on vascular endothelium during development. This review summarizes our current knowledge of the cellular and molecular mechanisms involved in the development and maintenance of the BBB.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1A–C.
Fig. 2.
Fig. 3.

Similar content being viewed by others

References

  • Abbott NJ (1991) Permeability and transport of glial blood-brain barriers. Ann N Y Acad Sci 633:378–394

    CAS  PubMed  Google Scholar 

  • Achen MG, Clauss M, Schnürch H, Risau W (1995) The non-receptor tyrosine kinase Lyn is localized in the developing blood-brain barrier. Differentiation 59:15–24

    Article  CAS  PubMed  Google Scholar 

  • Adams RH (2002) Vascular patterning by Eph receptor tyrosine kinases and ephrins. Semin Cell Dev Biol 13:55–60

    Article  CAS  PubMed  Google Scholar 

  • Albrecht U, Seulberger H, Schwarz H, Risau W (1990) Correlation of blood-brain barrier function and HT7 protein distribution in chick brain circumventricular organs. Brain Res 535:49–61

    PubMed  Google Scholar 

  • Bär T (1980) The vascular system of the cerebral cortex. Adv Anat Embryol Cell Biol 59:1–62

    Google Scholar 

  • Barber AJ, Lieth E (1997) Agrin accumulates in the brain microvascular basal lamina during development of the blood-brain barrier. Dev Dyn 208:62–74

    CAS  PubMed  Google Scholar 

  • Bass T, Singer G, Slusser J, Liuzzi FJ (1992) Radial glial interaction with cerebral germinal matrix capillaries in the fetal baboon. Exp Neurol 118:126–132

    CAS  PubMed  Google Scholar 

  • Bauer HC, Bauer H (2000) Neural induction of the blood-brain barrier: still an enigma. Cell Mol Neurobiol 20:13–28

    Article  CAS  PubMed  Google Scholar 

  • Bendayan R, Lee G, Bendayan M (2002) Functional expression and localization of P-glycoprotein at the blood brain barrier. Microsc Res Tech 57:365–380

    Article  CAS  PubMed  Google Scholar 

  • Bertossi M, Girolamo F, Errede M, Benagiano V, Virgintino D, Roncali L (2002) Developmental changes of HT7 expression in the microvessels of the chick embryo brain. Anat Embryol 205:229–233

    Article  CAS  PubMed  Google Scholar 

  • Betz AL, Goldstein GW (1986) Specialized properties and solute transport in brain capillaries. Annu Rev Physiol 48:241–250

    Article  CAS  PubMed  Google Scholar 

  • Biedl A, Kraus R (1898) Über eine bisher unbekannte toxische Wirkung der Gallensäure auf das Zentralnervensystem. Zentralbl Inn Med 19:1185–1200

    Google Scholar 

  • Bolton SJ, Anthony DC, Perry VH (1998) Loss of tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood-brain barrier breakdown in vivo. Neuroscience 86:1245–1257

    Article  CAS  PubMed  Google Scholar 

  • Bolz S, Farrell CL, Dietz K, Wolburg H (1996) Subcellular distribution of glucose transporter (GLUT-1) during development of the blood-brain barrier in rats. Cell Tissue Res 284:355–365

    Article  CAS  PubMed  Google Scholar 

  • Bouchaud C, Bosler O (1986) The circumventricular organs of the mammalian brain with special reference to monoaminergic innervation. Int Rev Cytol 105:283–327

    CAS  PubMed  Google Scholar 

  • Bradbury M (1979) The concept of a blood-brain barrier. Wiley, Chichester

  • Breier G, Breviaro F, Caveda L, Berthier R, Schnürch H, Gotsch U, Vestweber D, Risau W, Dejana E (1996) Molecular cloning and expression of murine VE-cadherin in early developing cardiovascular system Blood 87:630–641

  • Brightman MW, Reese TS (1969) Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 40:648–677

    CAS  PubMed  Google Scholar 

  • Broadwell RD (1989) Transcytosis of macromolecules through the blood-brain barrier: a cell biological perspective and critical appraisal. Acta Neuropathol (Berl) 79:117–128

    Google Scholar 

  • Butt AM, Jones HC, Abbott NJ (1990) Electrical-resistance across the blood-brain-barrier in anesthetized rats—a developmental study. J Physiol 429:47–62

    CAS  PubMed  Google Scholar 

  • Carmeliet P, Collen D (2000) Molecular basis of angiogenesis. Role of VEGF and VE-cadherin. Ann N Y Acad Sci 902:49–62

    Google Scholar 

  • Cecchelli R, Dehouck B, Descamps L, Fenart L, Buee-Scherrer V, Duhem C, Lundquist S, Rentfel M, Torpier G, Dehouck MP (1999) In vitro model for evaluating drug transport across the blood-brain barrier. Adv Drug Deliv Rev 36:165–178

    Article  CAS  PubMed  Google Scholar 

  • Claus P, Grothe C (2001) Molecular cloning and developmental expression of rat fibroblast growth factor receptor 3. Histochem Cell Biol 115:147–55

    CAS  PubMed  Google Scholar 

  • Corada M, Mariotti M, Thurston G, Smith K, Kunkel R, Brockhaus M, Lampugnani MG, Martin-Padura I, Stoppacciaro A, Ruco L, McDonald DM, Ward PA, Dejana E (1999) Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo. Proc Natl Acad Sci USA 96:9815–9820

    CAS  PubMed  Google Scholar 

  • Crone C, Olesen SP (1982) Electrical resistance of brain microvascular endothelium. Brain Res 241:49–55

    Article  CAS  PubMed  Google Scholar 

  • Cserr HF, Bundgaard M (1984) Blood-brain interfaces in vertebrates: comparative approach. Am J Physiol 246:277–288

    Google Scholar 

  • Cucullo L, McAllister MS, Kight K, Krizanac-Bengez L, Marroni M, Mayberg MR, Stanness KA, Janigro D (2002) A new dynamic in vitro model for the multidimensional study of astrocyte-endothelial cell interactions at the blood-brain barrier. Brain Res 951:243–254

    Article  CAS  PubMed  Google Scholar 

  • Davis S, Yancopoulos GD (1999) The angiopoietins: Yin and Yang in angiogenesis. Curr Top Microbiol Immunol 237:173–185

    CAS  PubMed  Google Scholar 

  • Dejana E (1996) Endothelial adherens junctions: implications in the control of vascular permeability and angiogenesis. J Clin Invest 98:1949–1953

    CAS  PubMed  Google Scholar 

  • Dermietzel R, Krause D (1991) Molecular anatomy of the blood-brain-barrier as defined by immunocytochemistry. Int Rev Cytol 127:57–109

    CAS  PubMed  Google Scholar 

  • Dermietzel R, Krause D, Kremer M, Wang C, Stevenson B (1992) Pattern of glucose transporter (Glut 1) expression in embryonic brains is related to maturation of blood-brain barrier tightness. Dev Dyn 193:152–163

    CAS  PubMed  Google Scholar 

  • Duncan GS, Andrew DP, Takimoto H, Kaufman SA, Yoshida H, Spellberg J, Luis de la Pompa J, Elia A, Wakeham A, Karan-Tamir B, Muller WA, Senaldi G, Zukowski MM, Mak TW (1999) Genetic evidence for functional redundancy of platelet/endothelial cell adhesion molecule-1 (PECAM-1): CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions. J Immunol 162: 3022–3030

    CAS  PubMed  Google Scholar 

  • Ehrlich P (1904) Über die Beziehung chemischer Constitution, Vertheilung, und pharmakologischer Wirkung. Gesammelte Arbeiten zur Immunitätsforschung, Berlin

  • Emoto N, Gonzalez AM, Walicke PA, Wada E, Simmons DM, Shimasaki S, Baird A (1989) Basic fibroblast growth factor (FGF) in the central nervous system: identification of specific loci of basic FGF expression in the rat brain. Growth Factors 2:21–29

    CAS  PubMed  Google Scholar 

  • Engelhardt B (2001) The choroid plexus in health and disease. Microsc Res Tech 52:112–129

    Google Scholar 

  • Engelhardt B, Risau W (1995) The development of the blood-brain barrier. In: Greenwood J, Begley D, Segal M (eds) The development of the blood-brain barrier. Plenum, London, pp 10–100

  • Engelhardt B, Conley FK, Butcher EC (1994) Cell adhesion molecules on vessels during inflammation in the mouse central nervous system. J Neuroimmunol 51:199–208

    Article  CAS  PubMed  Google Scholar 

  • Farrell CL, Risau W (1994) Normal and abnormal development of the blood-brain barrier. Microsc Res Tech 27:495–506

    CAS  PubMed  Google Scholar 

  • Ferrara N, Henzel WJ (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161:851–858

    CAS  PubMed  Google Scholar 

  • Folkman J, Klagsbrun M (1987) Vascular physiology. A family of angiogenic peptides. Nature 329:671–672

    CAS  PubMed  Google Scholar 

  • Folkman J, Klagsbrun M, Sasse J, Wadzinski M, Ingber D, Vlodavsky I (1988) A heparin-binding angiogenic protein—basic fibroblast growth factor—is stored within basement membrane. Am J Pathol 130:393–400

    CAS  Google Scholar 

  • Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S (1993) Occludin—a novel integral membrane-protein localizing at tight junctions. J Cell Biol 123:1777–1788

    CAS  PubMed  Google Scholar 

  • Furuse M, Sasaki H, Tsukita S (1999) Manner of interaction of heterogeneous claudin species within and between tight junction strands. J Cell Biol 147:891–903

    CAS  PubMed  Google Scholar 

  • Gale NW, Yancopoulos GD (1999) Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 13:1055–1066

    PubMed  Google Scholar 

  • Gerhardt H, Liebner S, Wolburg H (1996) The pecten oculi of the chicken as a new in vivo model of the blood-brain barrier. Cell Tissue Res 285:91–100

    PubMed  Google Scholar 

  • Gerhardt H, Liebner S, Redies C, Wolburg H (1999) N-cadherin expression in endothelial cells during early angiogenesis in the eye and brain of the chicken: relation to blood-retina and blood-brain barrier development. Eur J Neurosci 11:1191–1201

    Article  CAS  PubMed  Google Scholar 

  • Gerhardt H, Wolburg H, Redies C (2000) N-cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken. Dev Dyn 218:472–479

    CAS  PubMed  Google Scholar 

  • Golden PL, Pardridge WM (2000) Brain microvascular P-glycoprotein and a revised model of multidrug resistance in brain. Cell Mol Neurobiol 20:165–181

    Article  CAS  PubMed  Google Scholar 

  • Goldmann EE (1913) Vitalfärbung am Zentralnervensystem. Abh Preuss Wissensch Phys Math 1:1–60

    Google Scholar 

  • Goldstein GW (1988) Endothelial cell-astrocyte interactions. A cellular model of the blood-brain barrier. Ann N Y Acad Sci 529:31–39

    CAS  PubMed  Google Scholar 

  • Hallmann R, Mayer DN, Berg EL, Broermann R, Butcher EC (1995) Novel mouse endothelial cell surface marker is suppressed during differentation of the blood-brain barrier. Dev Dyn 202:325–332

    CAS  PubMed  Google Scholar 

  • Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N (1992) Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 267:26031–26037

    CAS  PubMed  Google Scholar 

  • Ikeda E, Flamme I, Risau W (1996) Developing brain cells produce factors capable of inducing the HT7 antigen, a blood-brain barrier-specific molecule, in chick endothelial cells. Neurosci Lett 209:149–152

    PubMed  Google Scholar 

  • Janzer RC, Raff MC (1987) Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325:253–257

    Google Scholar 

  • Keep RF, Ennis SR, Beer ME, Betz AL (1995) Developmental changes in blood-brain barrier potassium permeability in the rat: relation to brain growth. J Physiol (Lond) 488:439–448

    Google Scholar 

  • Kissel K, Hamm S, Schulz M, Vecchi A, Garlanda C, Engelhardt B (1998) Immunohistochemical localization of the murine transferrin receptor (TfR) on blood-tissue barriers using a novel anti-TfR monoclonal antibody. Histochem Cell Biol110:63–72

    Article  Google Scholar 

  • Kniesel U, Wolburg H (2000) Tight junctions of the blood-brain barrier. Cell Mol Neurobiol 20:57–76

    Article  CAS  PubMed  Google Scholar 

  • Kniesel U, Risau W, Woburg H (1996) Development of blood-brain barrier tight junctions in the rat cortex. Dev Brain Res 96:229–240

    Article  CAS  Google Scholar 

  • Kuban KC, Gilles FH (1985) Human telencephalic angiogenesis. Ann Neurol 17:539–548

    CAS  PubMed  Google Scholar 

  • Leonhardt H (1980) Ependym und circumventriculäre Organe. In: Oksche A, Vollrath L (eds) Handbuch der mikroscopischen Anatomie des Menschen, vol IV, chap 10. Springer, Berlin Heidelberg New York, pp 177–666

  • Lewandowsky M (1890) Zur Lehre der Zerebrospinalflüssigkeit. Z Klin Med 40:480–494

    Google Scholar 

  • Liebner S, Gerhardt H, Wolburg H (2000) Differential expression of endothelial beta-catenin and plakoglobin during development and maturation of the blood-brain and blood-retina barrier in the chicken. Dev Dyn 271:86–98

    Article  Google Scholar 

  • Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245

    Article  CAS  PubMed  Google Scholar 

  • Martin-Padura I, Lostaglio S, Schneemann M, Williams L, Romano M, Fruscella P, Panzeri C, Stoppacciaro A, Ruco L, Villa A, Simmons D, Dejana E (1998) Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol142:117–127

    Article  Google Scholar 

  • McCarty JH, Monahan-Earley RA, Brown LF, Keller M, Gerhardt H, Rubin K, Shani M, Dvorak HF, Wolburg H, Bader BL, Dvorak AM, Hynes RO (2002) Defective associations between blood vessels and brain parenchyma lead to cerebral hemorrhage in mice lacking alphav integrins. Mol Cell Biol 22:7667–7777

    Article  CAS  PubMed  Google Scholar 

  • Meresse S, Dehouck MP, Delorme P, Bensaid M, Tauber JP, Delbart C, Fruchart JC, Cecchelli R (1989) Bovine brain endothelial cells express tight junctions and monoamine oxidase activity in long-term culture. J Neurochem 53:1363–1371

    CAS  PubMed  Google Scholar 

  • Mollgard K, Dziegielewska KM, Saunders NR, Zakut H, Soreq H (1988) Synthesis and localization of plasma proteins in the developing human brain. Integrity of the fetal blood-brain barrier to endogenous proteins of hepatic origin. Dev Biol 128:207–221

    CAS  PubMed  Google Scholar 

  • Morita K, Furuse M, Fujimoto K, Tsukita S (1999a) Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc Natl Acad Sci USA 96:511–516

    CAS  PubMed  Google Scholar 

  • Morita K, Sasaki H, Furuse M, Tsukita S (1999b) Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J Cell Biol 147:185–194

    Article  CAS  PubMed  Google Scholar 

  • Mühleisen H, Wolburg H, Betz E (1989) Freeze-fracture analysis of endothelial cell membranes in rabbit carotid arteries subjected to short-term atherogenic stimuli. VirchArch [B] Cell Pathol 56:413–417

  • Nasdala I, Wolburg-Buchholz K, Wolburg H, Kuhn A, Ebnet K, Brachtendorf G, Samulowitz U, Kuster B, Engelhardt B, Vestweber D, Butz S (2002) A transmembrane tight junction protein selectively expressed on endothelial cells and platelets. J Biol Chem 277:16294–16303

    Article  CAS  PubMed  Google Scholar 

  • Noden DM (1991) Development of craniofacial blood vessels. In: Feinberg RN, Sherer GK, Auerbach R (eds) Development of craniofacial blood vessels. Karger, Basel, pp 1–24

  • Olsson Y, Klatzo I, Sourander P, Steinwall O (1968) Blood-brain barrier to albumin in embryonic new born and adult rats. Acta Neuropathol 10:117–122

    CAS  PubMed  Google Scholar 

  • Pardridge WM (1988) Recent advances in blood-brain barrier transport. Annu Rev Pharmacol Toxicol 28:25–39

    Article  CAS  PubMed  Google Scholar 

  • Phelps CH (1972) The development of glio-vascular relationships in the rat spinal cord. Z Zellforsch 128:555–563

    CAS  Google Scholar 

  • Qin Y, Sato TN (1995) Mouse multidrug resistance 1a/3 gene is the earliest known endothelial cell differentiation marker during blood-brain barrier development. Dev Dyn 202:172–180

    CAS  PubMed  Google Scholar 

  • Rascher G, Fischmann A, Kröger S, Duffner F, Grote E-H, Wolburg H (2002) Extracellular matrix and the blood-brain barrier in glioblastoma multiforme: spatial segregation of tenascin and agrin. Acta Neuropathol 104:85–91

    Article  CAS  PubMed  Google Scholar 

  • Reese TS, Karnovsky MJ (1967) Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34:207–217

    CAS  PubMed  Google Scholar 

  • Risau W (1991) Induction of blood-brain barrier endothelial cell differentiation. Ann N Y Acad Sci 633:405–419

    CAS  PubMed  Google Scholar 

  • Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674

    CAS  PubMed  Google Scholar 

  • Risau W, Wolburg H (1990) Development of the blood-brain-barrier. Trends Neurosci 13:174–178

    Article  CAS  PubMed  Google Scholar 

  • Risau W, Wolburg H (1991) The importance of the blood-brain-barrier in fetuses and embryos—reply. Trends Neurosci 14:15

    Article  Google Scholar 

  • Risau W, Hallmann R, Albrech U (1986a) Differentiation-dependent expression of protein in brain endothelium during development of the blood-brain barrier. Dev Biol 117:537–545

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Risau W, Gautschi-Sova P, Bohlen P (1988a) Endothelial cell growth factors in embryonic and adult chick brain are related to human acidic fibroblast growth factor. EMBO J 7:959–962

    CAS  PubMed  Google Scholar 

  • Risau W, Gautschi-Sova P, Böhlen P (1988b) Endothelial cell growth factors in embryonic and adult chick brain are related to human acidic fibroblast growth factors. EMBO J 7:959–962

    CAS  PubMed  Google Scholar 

  • Robertson PL, Du Bois M, Bowman PD, Goldstein GW (1985) Angiogenesis in developing rat brain: an in vivo and in vitro study. Dev Brain Res 23:219–223

    Article  Google Scholar 

  • Roncali L, Nico B, Ribatti D, Bertossi M, Mancini L (1986) Microscopical and ultrastructural investigations on the development of the blood-brain barrier in the chick embryo optic tectum. Acta Neuropathol (Berl) 70:193–201

    Google Scholar 

  • Rubin LL, Hall DE, Porter S, Barbu K, Cannon C, Horner HC, Janatpour M, Liaw CW, Manning K, Morales J, Tanner LI, Tomaselli KJ, et al (1991) A cell-culture model of the blood-brain-barrier. J Cell Biol 115:1725–1735

    CAS  PubMed  Google Scholar 

  • Ruhrberg C, Gerhardt H, Golding M, Watson R, Ioannidou S, Fujisawa H, Betsholtz C, Shima DT (2002) Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev 16:2684–2698

    Article  CAS  PubMed  Google Scholar 

  • Saitou M, Furuse M, Sasaki H, Schulzke J-D, Fromm M, Takano H, Noda T, Tsukita S (2000) Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol Biol Cell 22:4131–4142

    Google Scholar 

  • Saunders NR, Dziegielewska KM, Mollgard K (1991) Letter to the editor: the importance of the blood-brain barrier in fetuses and embryos. Trends Neurosci 14:14–15

    Article  CAS  PubMed  Google Scholar 

  • Schinkel AH, Smit JJM, Tellingen O van, Beijnen JH, Wagenaar E, Deemter L van, Mol CAAM, Walk MA van der, Robanus-Maandag EC, Riele HPJ te, Berns AJM, Borst P (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491–502

    CAS  PubMed  Google Scholar 

  • Schnürch H, Risau W (1991) Differentiating and mature neurons express the acidic fibroblast growth factor gene during chick neural development. Development 111:1143–1154

    PubMed  Google Scholar 

  • Schulze C, Firth JA (1992) Interendothelial junctions during blood-brain barrier development in the rat: morphological changes at the level of individual tight junctional contacts. Dev Brain Res 10:1–11

    Google Scholar 

  • Schulze C, Firth JA (1993) Immunohistochemical localization of adherens junction components in blood-brain-barrier microvessels of the rat. J Cell Sci 104:773–782

    PubMed  Google Scholar 

  • Seulberger H, Unger CM, Risau W (1992) HT7, Neurothelin, Basigin, gp42 and OX-47—many names for one developmentally regulated immuno-globulin-like surface glycoprotein on blood-brain barrier endothelium, epithelial tissue barriers and neurons. Neurosci Lett 140:93–97

    Article  CAS  PubMed  Google Scholar 

  • Simionescu M, Ghinea N, Fixman A, Lasser M, Kukes L, Simionescu N, Palade GE (1988) The cerebral microvasculature of the rat: structure and luminal surface properties during early development. J Submicrosc Cytol 20:243–261

    CAS  Google Scholar 

  • Sims DE (1986) The pericyte—a review. Tissue Cell 18:153–174

    CAS  PubMed  Google Scholar 

  • Small RK, Watkins BA, Munro PM, Liu D (1993) Functional properties of retinal Muller cells following transplantation to the anterior eye chamber. Glia 7:158–169

    CAS  PubMed  Google Scholar 

  • Stan RV, Ghitescu L, Jacobson BS, Palade GE (1999) Isolation, cloning, and localization of rat PV-1, a novel endothelial caveolar protein. J Cell Biol 145:1189–1198

    Article  CAS  PubMed  Google Scholar 

  • Stewart PA (2000) Development of the blood-brain barrier. In Risau W, Rubanyi GM (eds), Development of the blood-brain barrier. Harwood, Amsterdam, pp 109–122

  • Stewart PA, Hayakawa EM (1987) Interendothelial junctional changes underlie the developmental "tightening" of the blood-brain barrier. Dev Brain Res 32:271–281

    Article  Google Scholar 

  • Stewart PA, Hayakawa EM (1994) Early ultrastructural changes in blood-brain barrier vessels of the rat embryo. Dev Brain Res 78:25–34

    Article  CAS  Google Scholar 

  • Stewart PA, Wiley MJ (1981) Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail-chick transplantation chimeras. Dev Biol 84:183–192

    CAS  PubMed  Google Scholar 

  • Stewart PA, Beliveau R, Rogers KA (1996) Cellular localization of P-glycoprotein in brain versus gonadal capillaries. J Histochem Cytochem 44:679–685

    CAS  PubMed  Google Scholar 

  • Stonestreet BS, Patlak CS, Pettigrew KD, Reilly CB, Cserr HF (1996) Ontogeny of blood-brain barrier function in ovine fetuses, lambs, and adults. Am J Physiol 271:R1594–R1601

    CAS  PubMed  Google Scholar 

  • Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87:1171–1180

    CAS  PubMed  Google Scholar 

  • Tsukita S, Furuse M, Itoh M (1999) Structural and signalling molecules come together at tight junctions. Curr Opin Cell Biol 11:628–633

    CAS  PubMed  Google Scholar 

  • Tuor UI, Simone C, Bascaramurty S (1992) Local blood-brain barrier in the newborn rabbit: postnatal changes in alpha-aminoisobutyric acid transfer within medulla, cortex, and selected brain areas. J Neurochem 59:999–1007

    CAS  PubMed  Google Scholar 

  • Vleminckx K, Kemler R (1999) Cadherins and tissue formation: integrating adhesion adn signaling. Bioessays 21:211–220

    Article  CAS  PubMed  Google Scholar 

  • Wakai S, Hirokawa N (1978) Development of the blood-brain barrier to horseradish peroxidase in the chick embryo. Cell Tissue Res 195:195–203

    PubMed  Google Scholar 

  • Wolburg H, Lippoldt A (2002) Tight junctions of the blood-brain barrier: development, composition and regulation. Vasc Pharmacol 28:323–337

    Article  Google Scholar 

  • Wolburg H, Neuhaus J, Kniesel U, Krauss B, Schmid EM, Ocalan M, Farrell C, Risau W (1994) Modulation of tight junction structure in blood-brain-barrier endothelial-cells—effects of tissue-culture, 2nd messengers and cocultured astrocytes. J Cell Sci 107:1347–1357

    CAS  PubMed  Google Scholar 

  • Wolburg H, Wolburg-Buchholz K, Kraus J, Rascher-Eggstein G, Liebner S, Hamm S, Duffner F, Grote E-H, Risau W, Engelhardt B (2003) Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme. Acta Neuropathol 105:586–592

    Google Scholar 

  • Zhu J, Motejlek K, Wang D, Zang K, Schmidt A, Reichardt LF (2002) Abstract beta8 integrins are required for vascular morphogenesis in mouse embryos. Development 129:2891–2903

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I owe many thanks to Urban Deutsch for his critical discussion of this manuscript.

Author information

Authors and Affiliations

  1. Max Planck Institute for Vascular Biology, von-Esmarch-Strasse 56, 48149, Münster, Germany

    Britta Engelhardt

Authors
  1. Britta Engelhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Britta Engelhardt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Engelhardt, B. Development of the blood-brain barrier. Cell Tissue Res 314, 119–129 (2003). https://doi.org/10.1007/s00441-003-0751-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-003-0751-z

Keywords

Search

Navigation