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The Nature and Composition of the Internal Environment of the Developing Brain

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Abstract

1. The fetal brain develops within its own environment, which is protected from free exchange of most molecules among its extracellular fluid, blood plasma, and cerebrospinal fluid (CSF) by a set of mechanisms described collectively as “brain barriers.”

2. There are high concentrations of proteins in fetal CSF, which are due not to immaturity of the blood–CSF barrier (tight junctions between the epithelial cells of the choroid plexus), but to a specialized transcellular mechanism that specifically transfers some proteins across choroid plexus epithelial cells in the immature brain.

3. The proteins in CSF are excluded from the extracellular fluid of the immature brain by the presence of barriers at the CSF–brain interfaces on the inner and outer surfaces of the immature brain. These barriers are not present in the adult.

4. Some plasma proteins are present within the cells of the developing brain. Their presence may be explained by a combination of specific uptake from the CSF and synthesis in situ.

5. Information about the composition of the CSF (electrolytes as well as proteins) in the developing brain is of importance for the culture conditions used for experiments with fetal brain tissue in vitro, as neurons in the developing brain are exposed to relatively high concentrations of proteins only when they have cell surface membrane contact with CSF.

6. The developmental importance of high protein concentrations in CSF of the immature brain is not understood but may be involved in providing the physical force (colloid osmotic pressure) for expansion of the cerebral ventricles during brain development, as well as possibly having nutritive and specific cell development functions.

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REFERENCES

  • Abe, T., Kommatsu, M., Takeishi, M., and Tsunekane, T. (1976). The alpha-fetoprotein level in sera of bovine fetuses and calves. Jap. J. Vet. Sci. 38:339–345.

    Google Scholar 

  • Adinolfi, M., and Haddad, S. A. (1977). Levels of plasma proteins in human and rat fetal CSF and the development of the blood-CSF barrier. Neuropediatrie 8:345–353.

    Google Scholar 

  • Al-Sarraf, H., Preston, J. E., and Segal, M. B. (1995). The entry of acidic amino acids into brain and CSF during development, using in situ perfusion in the rat. Dev. Brain Res. 90:151–158.

    Google Scholar 

  • Åmtorp, O., and Sørensen, S. C. (1974). The ontogenetic development of concentration differences for protein and ions between plasma and cerebrospinal fluid in rabbits and rats. J. Physiol. 243:387–400.

    PubMed  Google Scholar 

  • Balslev, Y., Dziegielewska, K. M., Møllgård, K., and Saunders, N. R. (1997a). Intercellular barriers to and transcellular transfer of protein albumin in the fetal sheep. Anat. Embryol. 195:229–236.

    PubMed  Google Scholar 

  • Balslev, Y., Saunders, N. R., and Møllgård, K. (1997b). The surface CSF-brain barrier in the developing rat brain. J. Neurocytol. 26:133–148.

    PubMed  Google Scholar 

  • Baños, G., Daniel, P. M., and Pratt, O. E. (1978). The effect of age upon the entry of some amino acids into the brain, and their incorporation into cerebral protein. Dev. Med. Child Neurol. 20:335–346.

    PubMed  Google Scholar 

  • Bauer, H. (1998). Glucose transporters in mammalian brain development. In Pardridge, W. M. (ed.), An Introduction to the Blood-Brain Barrier, Cambridge University Press, Cambridge, pp. 175–187.

    Google Scholar 

  • Bauer, H., Sonnleitner, U., Lametschwandtner, A., Steiner, M., Adam, H., and Bauer, H. C. (1995). Ontogenic expression of the erythroid-type glucose transporter (Glut 1) in the telencephalon of the mouse: Correlation to the tightening of the blood-brain barrier. Dev. Brain Res. 86:317–325.

    Google Scholar 

  • Bayer, S. A., and Altman, J. (1991). Neocortical Development, Raven, New York.

    Google Scholar 

  • Bergmann, F. H., Levine, L., and Spiro, R. G. (1962). Fetuin: Immunocytochemistry and quantitative estimation in serum. Biochim. Biophys. Acta 58:41–51.

    PubMed  Google Scholar 

  • Birge, W. J., Rose, A. D., Haywood, J. R., and Doolin, P. F. (1974). Development of the bloodcerebrospinal fluid barrier to proteins and differentiation of cerebrospinal fluid in the chick embryo. Dev. Biol. 41:245.

    PubMed  Google Scholar 

  • Bloch, B., Popovici, T., Levin, M. J., Tuil, D., and Kahn, A. (1985). Transferrin gene expression visualized in oligodendrocytes of the rat brain by using in situ hybridization and immunohistochemistry. Proc. Natl. Acad. Sci. USA 82:6706–6710.

    PubMed  Google Scholar 

  • Bradbury, M. W. B. (1979). The Concept of the Blood-Brain Barrier, John Wiley, Chichester.

    Google Scholar 

  • Bradbury, M. W. B., Crowder, J., Desai, S., Reynolds, J. M., Reynolds, M. L., and Saunders, N. R. (1972). Electrolytes and water in the brain and cerebrospinal fluid of the foetal sheep and guinea pig. J. Physiol. 227:591–610.

    PubMed  Google Scholar 

  • Braun, L. D., Cornford, E. M., and Oldendorf, W. H. (1980). Newborn rabbit blood-brain barrier is selectively permeable and differs substantially from the adult. J. Neurochem. 34:147–152.

    PubMed  Google Scholar 

  • Brenton, D. P., and Gardiner, R. M. (1988). Transport of L-phenylalanine and related amino acids at the ovine blood-brain barrier. J. Physiol. 402:497–514.

    PubMed  Google Scholar 

  • Brightman, M. W., and Reese, T. S. (1969). Junctions between intimately apposed cell membranes in the vertebrate brain. J. Cell Biol. 40:648–677.

    PubMed  Google Scholar 

  • Brown, W. M., Saunders, N. R., Møllgård, K., and Dziegielewska, K. M. (1992). Fetuin an old friend revisited. Bioessays 14:749–755.

    PubMed  Google Scholar 

  • Butt, A. M., Jones, H. C., and Abbott, N. J. (1990). Electrical resistance across the blood-brain barrier in anaesthetized rats: A developmental study. J. Physiol. 429:47–62.

    PubMed  Google Scholar 

  • Cavanagh, M. E., and Møllgård, K. (1985). An immunocytochemical study of the distribution of some plasma proteins within the developing forebrain of the pig with special reference to the neocortex. Dev. Brain Res. 17:183–194.

    Google Scholar 

  • Cavanagh, M. E., Cornelis, M. E., Dziegielewska, K. M., Luft, A. J., Lai, P. C. W., Lorscheider, F. L., and Saunders, N. R. (1982). Proteins in cerebrospinal fluid and plasma of fetal pigs during development. Dev. Neurosci. 5:492–502.

    PubMed  Google Scholar 

  • Cornford, E. M., Braun, L. D., and Oldendorf, W. H. (1982). Developmental modulations of bloodbrain barrier permeability as an indicator of changing nutritional requirements in the brain. Pediatr. Res. 16:324–328.

    PubMed  Google Scholar 

  • Cornford, E. M., Hyman, S., and Landaw, E. M. (1994). Developmental modulation of blood-brainbarrier glucose transport in the rabbit. Brain Res. 663:7–18.

    PubMed  Google Scholar 

  • Crowe, A., and Morgan, E. H. (1992). Iron and transferrin uptake by brain and cerebrospinal fluid in the rat. Brain Res. 592:8–16.

    PubMed  Google Scholar 

  • Daniel, P. M., Love, E. R., and Pratt, O. E. (1978). The effect of age upon the influx of glucose into the brain. J. Physiol. 274:141–148.

    PubMed  Google Scholar 

  • Davies, A. D., and Temple, S. (1994). A self-renewing multipotential stem cell in embryonic rat cerebral cortex. Nature 372:263–266.

    PubMed  Google Scholar 

  • Davson, H., and Segal, M. B. (1996). Physiology of the CSF and Blood-Brain Barriers, CRC Press, Boca Raton, FL.

  • Desmond, M. E., and Jacobsen, A. G. (1977). Embryonic brain enlargement requires cerebrospinal fluid pressure. Dev. Biol. 57:188–198.

    PubMed  Google Scholar 

  • Dziegielewska, K. M. (1982). Proteins in Fetal CSF and Plasma, Ph.D. thesis, University of London, London.

    Google Scholar 

  • Dziegielewska, K. M., and Brown, W. M. (1995). Fetuin, Molecular Biology Intelligence Unit, Springer Verlag, New York.

    Google Scholar 

  • Dziegielewska, K. M., and Saunders, N. R. (1988). The development of the blood-brain barrier: Proteins in fetal and neonatal CSF, their nature and origins. In Meisami, E., and Timiras, P. J. (eds.), Handbook of Human Growth and Developmental Biology, Vol. 1A, CRC, Boca Raton; FL, pp. 169–191.

    Google Scholar 

  • Dziegielewska, K. M., Evans, C. A. N., Malinowska, D., Møllgård, K., Reynolds, J. M., Reynolds, M. L., Saunders, N. R. (1979). Studies of the development of brain barrier systems to lipid insoluble molecules in fetal sheep. J. Physiol. 292:207–231.

    PubMed  Google Scholar 

  • Dziegielewska, K. M., Evans, C. A. N., Fossan, G., Lorscheider, F. L., Malinowska, D. H., Møllgård, K., Reynolds, M. L., and Saunders, N. R., and Wilkinson, S. (1980a). Proteins in cerebrospinal fluid and plasma of fetal sheep during development. J. Physiol. 300:441–455.

    PubMed  Google Scholar 

  • Dziegielewska, K. M., Evans, C. A. N., Malinowska, D. H., Møllgård, K., Reynolds, M. L., and Saunders, N. R. (1980b). Blood-cerebrospinal fluid transfer of plasma proteins during fetal development in the sheep. J. Physiol. 300:457–465.

    PubMed  Google Scholar 

  • Dziegielewska, K. M., Evans, C. A. N., Lai, P. C. W., Lorscheider, F. L., Malinowska, D. H., Møllgård, K., and Saunders, N. R. (1981). Proteins in cerebrospinal fluid and plasma of fetal rats during development. Dev. Biol. 83:192–200.

    Google Scholar 

  • Dziegielewska, K. M., Hinds, L. A., Møllgård, K., Reynolds, M. L., and Saunders, N. R. (1988). Bloodbrain, blood-cerebrospinal fluid and cerebrospinal fluid-brain barriers in a marsupial (Macropus eugenii) during development. J. Physiol. 403:367–388.

    PubMed  Google Scholar 

  • Dziegielewska, K. M., Habgood, M., Jones, S. E., Reader, M., and Saunders, N. R. (1989). Proteins in cerebrospinal fluid and plasma of postnatal Monodelphis domestica (Grey short-tailed opossum). Comp. Biochem. Physiol. 92B:569–576.

    Google Scholar 

  • Dziegielewska, K. M., Habgood, M. D., Møllgård, K., Stagaard, M., and Saunders, N. R. (1991). Species specific transfer of plasma albumin from blood into different cerebrospinal fluid compartments in the fetal sheep. J. Physiol. 439:215–237.

    PubMed  Google Scholar 

  • Dziegielewska, K. M., Brown, W. M., Gould, C. C., Matthews, N., Sedgwick, J. E. C., and Saunders, N. R. (1992). Fetuin: An acute phase protein in cattle. J. Comp. Physiol. B. 162:168–171.

    PubMed  Google Scholar 

  • Dziegielewska, K. M., Reader, M., Matthews, N., Brown, W. M., Møllgård, K., and Saunders, N. R. (1993). Synthesis of the fetal protein fetuin by early developing neurons in the immature neocortex. J. Neurocytol. 22:266–272.

    PubMed  Google Scholar 

  • Evans, C. A. N., Reynolds, J. M., Reynolds, M. L., Saunders, N. R., and Segal, M. B. (1974). The development of a blood-brain barrier mechanism in foetal sheep. J. Physiol. 238:371–386.

    Google Scholar 

  • Fielitz, W., Esteves, A., and Moro, R. (1984). Protein composition of cerebrospinal fluid in the developing chick embryo. Dev. Brain Res. 13:111.

    Google Scholar 

  • Fossan, G., Cavanagh, M. E., Evans, C. A. N., Malinowska, D. H., Møllgård, K., Reynolds, M. L., and Saunders. N. R. (1985). CSF-brain permeability in the immature sheep fetus: a CSF-brain barrier. Dev. Brain Res. 18:113–124.

    Google Scholar 

  • Habgood, M. D., Sedgwick, J. E. C., Dziegielewska, K. M., and Saunders, N. R. (1992). A developmentally regulated blood-cerebrospinal fluid transfer mechanism for albumin in immature rats. J. Physiol. 456:181–192.

    PubMed  Google Scholar 

  • Habgood, M. D., Knott, G. W., Dziegielewska, K. M., and Saunders, N. R. (1993). The nature of the decrease in blood-cerebrospinal fluid barrier exchange during postnatal brain development in the rat. J. Physiol. 468:73–83.

    PubMed  Google Scholar 

  • Habgood, M. D., Begley, D. J., and Abbott, N. J. (2000). Determination of passive entry into the nervous system. Cell. Mol. Neurobiol. 20:xx-xx.

    Google Scholar 

  • Jones, S. E., Christie, D. L., Dziegielewska, K. M., Hinds, L. A., and Saunders, N. R. (1991). Developmental profile of a fetuin-like glycoprotein in neocortex, cerebrospinal fluid and plasma of postnatal tammar wallaby (Macropus eugenii). Anat. Embryol. 183:313–320.

    PubMed  Google Scholar 

  • Knott, G. W. (1995). Barriers in the Developing Brain, Ph. D. thesis, University of Tasmania, pp. 1–159.

  • Knott, G. W., Dziegielewska, K. M., Habgood, M. D., Li, Z. S., and Saunders, N. R. (1997). Albumin transfer across the choroid plexus of South American opossum (Monodelphis domestica). J. Physiol. 499:179–194.

    PubMed  Google Scholar 

  • Lefauconnier, J.-M. (1992). Transport of amino acids. In Bradbury, M. W. B. (ed.), Physiology and Pharmacology of the Blood-Brain Barrier, Springer-Verlag, Berlin, pp. 117–150.

    Google Scholar 

  • Lehmenkühler, A., Syková, E., Svoboda, J., Zilles, K., and Nicholson, C. (1993). Extracellular space parameters in the rat neocortex and subcortical white matter during postnatal development determined by diffusion analysis, Neuroscience 55:339–351.

    PubMed  Google Scholar 

  • Li, M., Pevny, L., Lovell-Badge, R., and Smith, A. (1998). Generation of purified neural precursors from embryonic stem cells by lineage selection. Curr. Biol. 8:971–974.

    PubMed  Google Scholar 

  • Li, Z. S., Knott, G. W., Dziegielewska, K. M., Deal, A., and Saunders, N. R. (1997). Co-localisation of endogenous and exogenous fetuin in the neocortex of the fetal rat. Proc. Aust. Neurosci. Soc. 8:1–7.

    Google Scholar 

  • Maher, F., Vannucci, S. J., and Simpson, I. A. (1994). Glucose transporter proteins in brain. FASEB J. 8:1003–1011.

    PubMed  Google Scholar 

  • Møllgård, K., Malinowska, D. H., and Saunders, N. R. (1976). Lack of correlation between tight junction morphology and permeability properties in developing choroid plexus. Nature 264:293–294.

    PubMed  Google Scholar 

  • Møllgård, K., Reynolds, M. L., Jacobsen, M., Dziegielewska, K. M., and Saunders, N. R. (1984). Differential immunocytochemical staining for fetuin and transferrin in the developing cortical plate. J. Neurocytol. 13:497–502.

    PubMed  Google Scholar 

  • Møllgård, K., Balslev, Y., Lauritzen, B., and Saunders, N. R. (1987). Cell junctions and membrane specializations in the ventricular zone (germinal matrix) of the developing sheep brain: A CSF brain barrier. J. Neurocytol. 16:433–444.

    PubMed  Google Scholar 

  • Møllgård, K., Dziegielewska, K. M., Saunders, N. R., Zakut, H., and Soreq, H. (1988). Synthesis and localization of plasma proteins in the developing human brain. Dev. Biol. 128:207–221.

    PubMed  Google Scholar 

  • Moos, T., and Morgan, E. H. (2000). Transferrin and transferrin receptor function in brain barrier mechanisms. Cell. Mol. Neurobiol. 20:77–95.

    PubMed  Google Scholar 

  • Nadal, A., Fuentes, E., Pastor, J., and McNaughton, P. A. (1995). Plasma albumin is a potent trigger of calcium signals and DNA synthesis in astrocytes. Cell. Biol. 92:1426–1430.

    Google Scholar 

  • New, H., Dziegielewska, K. M., and Saunders, N. R. (1983). Transferrin in fetal rat brain and cerebrospinal fluid. Int. J. Dev. Neurosci. 1:369–373.

    Google Scholar 

  • Panrucker, D. E., Dziegielewska, K. M., Lorscheider, F. L., and Saunders, N. R. (1983). Acute phase α 2-macroglobulin in CSF during development of the fetal rat. Int. J. Dev. Neurosci. 1:31–34.

    Google Scholar 

  • Pardridge, W. M., and Boado, R. J. (1993). Molecular cloning and regulation of gene expression of blood-brain barrier glucose transporter. In Pardridge, W. M. (ed.), The Blood-Brain Barrier, Cell. Mol. Biol., Raven, New York, pp. 395–440.

    Google Scholar 

  • Pardridge, W. M., Boado, R. J., and Farrell, C. R. (1990). Brain-type glucose transporter (GLUT-1) is selectively localized to the blood-brain barrier. Studies with quantitative Western blotting and in situ hybridization. J. Biol. Chem. 265:18035–18040.

    PubMed  Google Scholar 

  • Ramey, B. A., and Birge, W. J. (1979). Development of cerebrospinal and the blood-cerebrospinal fluid barrier in rabbits. Dev. Biol. 68:292–298.

    PubMed  Google Scholar 

  • Rennels, M. L., Gregory, T. F., Blaumanis, O. R., Fujimoto, K., and Grady, P. A. (1985). Evidence for a “paravascular” fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res. 326:47–63.

    PubMed  Google Scholar 

  • Reynolds, M. L., and Møllgård, K. (1985). The distribution of plasma proteins in the neocortex and early allocortex of the developing sheep brain. Anat. Embryol. 171:41–60.

    PubMed  Google Scholar 

  • Saunders, N. R. (1992). Ontogenetic development of brain barrier mechanisms. In Bradbury, M. W. B. (ed.), Handbook of Experimental Pharmacology, Vol. 103. Physiology and Pharmacology of the Blood-Brain Barrier. Springer-Verlag, Berlin, Chap. 14.

    Google Scholar 

  • Saunders, N. R., and Dziegielewska, K. M. (1997). Barriers in the developing brain. News Physiol. Sci. 12:21–31.

    Google Scholar 

  • Saunders, N. R., Adam, E., Reader, M., and Møllgård, K. (1989). Monodelphis domestica (grey short-tailed opossum): An accessible model for studies of early neocortical development. Anat. Embryol. 180:227–236.

    PubMed  Google Scholar 

  • Saunders, N. R., Habgood, M. D., and Dziegielewska, K. M. (1999a). Barrier mechanisms in the brain. Part 1. Adult brain.Clin Exp. Pharmacol. Physiol. 26:11–19.

    PubMed  Google Scholar 

  • Saunders, N. R., Habgood, M. D., and Dziegielewska, K. M. (1999b). Barrier mechanisms in the brain. Part 2. The immature brain. Clin. Exp. Pharmacol. Physiol. 26:85–91.

    PubMed  Google Scholar 

  • Saunders, N. R., Knott, G. W., and Dziegielewska, K. M. (2000). Barriers in the immature brain. Cell. Mol. Neurobiol. 20:xx-xx.

    Google Scholar 

  • Syková, E., and Chvátal, A. (1992). Extracellular ionic and volume changes: The role in glia-neuron interaction. J. Chem. Neuroanat. 6:247–260.

    Google Scholar 

  • Syková, E., Jendelová, P., Simonová, Z., and Chvátal, A. (1992). K+ and pH homeostasis in the developing rat spinal cord is impaired by early postnatal X-irradiation. Brain Res. 594:19–30.

    PubMed  Google Scholar 

  • Taylor, E. M., and Morgan, E. H. (1990). Developmental changes in transferrin and iron uptake by the brain in the rat. Dev. Brain Res. 55:35–42.

    Google Scholar 

  • Van Essen, D. C. (1997). A tension-based theory of morphogenesis and compact wiring in the central nervous system. Nature. 385:313–318.

    PubMed  Google Scholar 

  • Vannucci, S. J. (1994). Developmental expression of GLUT1 and GLUT3 glucose transporters in rat brain. J. Neurochem. 62:240–246.

    PubMed  Google Scholar 

  • Vannucci, S. J., Seaman, L. B., Brucklacher, R. M., and Vannucci, R. C. (1994). Glucose transport in developing rat brain: Glucose transporter proteins, rate constants and cerebral glucose utilization. Mol. Cell. Biochem. 140:177–184.

    PubMed  Google Scholar 

  • Wagner, H. J., Pilgrim, C., and Brandl, J. (1974). Penetration and removal of horseradish peroxidase injected into the cerebrospinal fluid: Role of cerebral perivascular spaces, endothelium and microglia. Acta Neuropathol. (Berl.) 27:299–315.

    Google Scholar 

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  1. Anatomy and Physiology, University of Tasmania, GPO Box 252-24, Hobart, Tasmania, 7001, Australia

    Katarzyna M. Dziegielewska, Graham W. Knott & Norman R. Saunders

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  1. Katarzyna M. Dziegielewska
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Dziegielewska, K.M., Knott, G.W. & Saunders, N.R. The Nature and Composition of the Internal Environment of the Developing Brain. Cell Mol Neurobiol 20, 41–56 (2000). https://doi.org/10.1023/A:1006943926765

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