Molecular and Cellular Biochemistry

, Volume 212, Issue 1–2, pp 61–70 | Cite as

Norepinephrine transporter expression and function in noradrenergic cell differentiations

  • Maya Sieber-Blum
  • Zeguang Ren

Abstract

The classical view of norepinephrine transporter (NET) function is the re-uptake of released norepinephrine (NE) by mature sympathetic neurons and noradrenergic neurons of the locus ceruleus (LC; [1-3]). In this report we review previous data and present new results that show that NET is expressed in the young embryo in a wide range of neuronal and non-neuronal tissues and that NET has additional functions during embryonic development. Sympathetic neurons are derived from neural crest stem cells. Fibroblast growth factor-2 (FGF-2), neurotrophin-3 (NT-3) and transforming growth factor-β1 (TGF-β1) regulate NET expression in cultured quail neural crest cells by causing an increase in NET mRNA levels. They also promote NET function in both neural crest cells and presumptive noradrenergic cells of the LC. The growth factors are synthesized by the neural crest cells and therefore are likely to have autocrine function. In a subsequent stage of development, NE transport regulates differentiation of noradrenergic neurons in the peripheral nervous system and the LC by promoting expression of tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH). Conversely, uptake inhibitors, such as the tricyclic antidepressant, desipramine, and the drug of abuse, cocaine, inhibit noradrenergic differentiation in both tissues. Taken together, our data indicate that NET is expressed early in embryonic development, NE transport is involved in regulating expression of the noradrenergic phenotype in the peripheral and central nervous systems, and norepinephrine uptake inhibitors can disturb noradrenergic cell differentiation in the sympathetic ganglion (SG) and LC.

neural crest sympathetic ganglion locus ceruleus norepinephrine norepinephrine transporter tyrosine hydroxylase dopamine-beta-hydroxylase desipramine cocaine 

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References

  1. 1.
    Axelrod J: The metabolism, storage, and release of catecholamines. Rec Prog Horm Res 21: 597–619, 1965Google Scholar
  2. 2.
    Iversen LL: The Uptake and Storage of Noradrenaline in Sympathetic Nerves. Cambridge University Press, New York, 1967Google Scholar
  3. 3.
    Snyder SH: Putative neurotransmitters in the brain: Selective neuronal uptake, subcellular localization, and interactions with centrally acting drugs. Biol Psychiatry 2: 367–389, 1970Google Scholar
  4. 4.
    Sieber-Blum M: Inhibition of the adrenergic phenotype in cultured neural crest cells by norepinephrine uptake inhibitors. Dev Biol 136: 372–380, 1989Google Scholar
  5. 5.
    Zhang J-M, Sieber-Blum M: Characterization of the norepinephrine uptake system and the role of norepinephrine in the expression of the adrenergic phenotype by quail neural crest cells in clonal culture. Brain Res 570: 251–258, 1992Google Scholar
  6. 6.
    Strudel G, Recasens M, Mandel P: Identification de catecholamines et de serotonine dans les chordes d'embryons de poulet. CR Acad Sci Paris 284: 967–969, 1977Google Scholar
  7. 7.
    Rothman TP, Gershon MD, Holtzer H: The relationship of cell division to the acquisition of adrenergic characteristics by developing sympathetic ganglion cell precursors. Dev Biol 65: 322–341, 1978Google Scholar
  8. 8.
    Ren ZG, Pö rzgen P, Zhang J-M, Chen XR, Amara SG, Blakely RD, Sieber-Blum M: Autocrine regulation of NET expression. SubmittedGoogle Scholar
  9. 9.
    Sieber-Blum M, Cohen AM: Clonal analysis of quail neural crest cells: They are pluripotent and differentiate in vitro in the absence of noncrest cells. Dev Biol 80: 96–106, 1980Google Scholar
  10. 10.
    Sieber-Blum M: The neural crest colony assay: assessing molecular influences on development in culture. In: The Neuron in tissue Culture, IBRO. John Wiley & Sons Ltd. 1999, pp 5–22Google Scholar
  11. 11.
    Hamburger V, Hamilton H: A series of normal stages in the development of the chick embryo. J Morphol 88: 49–92, 1951Google Scholar
  12. 12.
    Zhang J-M, Dix J, Langtimm-Sedlak C, Trusk T, Schroeder B, Strosberg AD, Winslow JW, Sieber-Blum M: Neurotrophin-3 and norepinephrine-mediated adrenergic differentiation and the inhibitory action of desipramine and cocaine. J Neurobiol 32: 262–280, 1997Google Scholar
  13. 13.
    Gaese F, Kolbeck R, Barde Y-A: Sensory ganglia require neurotrophin-3 early in development. Development 120: 1613–1619, 1994Google Scholar
  14. 14.
    Panabieres F, Piechaczyk M, Rainer B, Dani C, Fort P, Riaad S, Marti L, Imbach JL, Jeanteur P, Blanchard J-MM: Complete nucelotide sequence of the messenger RNA coding for chicken muscle glyceraldehyde-3-phosphate dehydrogenase. Biochem Biophys Res Commun 118: 767–773, 1984Google Scholar
  15. 15.
    Schroeter S, Apparsundaram S, Wiley RG, Miner LAH, Sesack SR, Blakely RD: Immunolocalization of the cocaine-and antidepressantsensitive l-norepinephrine transporter. J Comp Neurol: 1999 (in press)Google Scholar
  16. 16.
    Sieber-Blum M: Commitment of neural crest cells to the sensory neuron lineage. Science 243: 1608–1611, 1989Google Scholar
  17. 17.
    Ren ZG, Pö rzgen P, Schroeter S, Amara S, Blakely R, Sieber-Blum M: Embryonic NET expression in the nervous and cardiovascular systems and in muscle cells. SubmittedGoogle Scholar
  18. 18.
    Guglielmone R, Panzica GC: Topographic, morphologic and developmental characterization of the nucleus loci coerulei in chicken. Cell Tissue Res 225: 95–110, 1982Google Scholar
  19. 19.
    Henion PD, Garner AS, Large TH, Weston JA: TrkC-mediated NT-3 signaling is required for the early development of a subpopulation of neurogenic neural crest cells. Dev Biol 172: 602–613, 1995Google Scholar
  20. 20.
    Merlio J-P, Ernfors P, Jaber M, Persson H: Molecular cloning of rat TrkC and identification of cells expressing mRNA for members of the trk family in the rat central nervous system. Neuroscience: 1992Google Scholar
  21. 21.
    Von Bartheld CS, Schober A, Kinoshita Y, Williams R, Ebendahl T, Bothwell T: Noradrenergic neurons in the locus ceruleus of birds express TrkA, transport, NGF, and respond to NGF. J Neurosci 15: 2225–2239, 1995Google Scholar
  22. 22.
    Shannon JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, Blakely RD, Robertson D: Orthostatic intolerance and tachycardia associated with norepinephrine transporter deficiency. New Engl J Med 432: 541–549, 2000Google Scholar
  23. 23.
    Amara SG, Kuhar MJ: Neurotransmitter transporters: Recent progress. Annu Rev Neurosci 16: 73–93, 1993Google Scholar
  24. 24.
    Lo L, Tiveron MC, Anderson DJ: MASH1 activates expression of the paired domain transcription factor Phx2a, and couples pan-neuronal and subtype-specific components of autonomic neuronal identity. Development 125: 609–620, 1998Google Scholar
  25. 25.
    Kim HS, Seo H, Yang C, Brunet JF, Kim KS: Noradrenergic-specific transcription of the dopamine beta-hydroxylase gene requires synergy of multiple cis-acting elements including at least two Phox2a-binding sites. J Neurosci 15: 8247–8260, 1998Google Scholar
  26. 26.
    Hurt H, Brodsky N, Betancourt L, Braitman LE, Malmud E, Giannetta J: Cocaine-exposed children: Follow-up through 30 months. J Dev Behav Ped 16: 29–35, 1995Google Scholar
  27. 27.
    Gingras JL, O'Donnell KJ, Hume RF: Maternal cocaine addiction and fetal behavioral state. I: A human model for the study of sudden infant death syndrome. Med Hypoth 33: 227–230, 1990Google Scholar
  28. 28.
    Gingrass JL, Weese-Mayer D: Maternal cocaine addiction. II: An animal model for the study of brainstem mechanisms operative in sudden infant death syndrome. Med Hypoth 33: 227–230, 1990Google Scholar
  29. 29.
    Gingrass JL, Weese-Mayer DE, Hume RF Jr, O'Donnell KJ: Cocaine and development: Mechanism of fetal toxicity and neonatal consequences of prenatal cocaine exposure. Early Hum Dev 31: 1–24, 1992Google Scholar
  30. 30.
    Hill RM, Tennyson LM: Maternal drug therapy: Effect on fetal and neonatal growth and neurobehavior. Neurol Toxicol 7: 121–140, 1986Google Scholar
  31. 31.
    Volpe JJ: Effect of cocaine use in the fetus. New Engl J Med 327: 399–407, 1992Google Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Maya Sieber-Blum
    • 1
  • Zeguang Ren
    • 1
  1. 1.Department of Cell Biology, Neurobiology and AnatomyMedical College of WisconsinMilwaukeeUSA

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