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.
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References
Axelrod J: The metabolism, storage, and release of catecholamines. Rec Prog Horm Res 21: 597–619, 1965
Iversen LL: The Uptake and Storage of Noradrenaline in Sympathetic Nerves. Cambridge University Press, New York, 1967
Snyder SH: Putative neurotransmitters in the brain: Selective neuronal uptake, subcellular localization, and interactions with centrally acting drugs. Biol Psychiatry 2: 367–389, 1970
Sieber-Blum M: Inhibition of the adrenergic phenotype in cultured neural crest cells by norepinephrine uptake inhibitors. Dev Biol 136: 372–380, 1989
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, 1992
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, 1977
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, 1978
Ren ZG, Pö rzgen P, Zhang J-M, Chen XR, Amara SG, Blakely RD, Sieber-Blum M: Autocrine regulation of NET expression. Submitted
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, 1980
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 5–22
Hamburger V, Hamilton H: A series of normal stages in the development of the chick embryo. J Morphol 88: 49–92, 1951
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, 1997
Gaese F, Kolbeck R, Barde Y-A: Sensory ganglia require neurotrophin-3 early in development. Development 120: 1613–1619, 1994
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, 1984
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)
Sieber-Blum M: Commitment of neural crest cells to the sensory neuron lineage. Science 243: 1608–1611, 1989
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. Submitted
Guglielmone R, Panzica GC: Topographic, morphologic and developmental characterization of the nucleus loci coerulei in chicken. Cell Tissue Res 225: 95–110, 1982
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, 1995
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: 1992
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, 1995
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, 2000
Amara SG, Kuhar MJ: Neurotransmitter transporters: Recent progress. Annu Rev Neurosci 16: 73–93, 1993
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, 1998
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, 1998
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, 1995
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, 1990
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, 1990
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, 1992
Hill RM, Tennyson LM: Maternal drug therapy: Effect on fetal and neonatal growth and neurobehavior. Neurol Toxicol 7: 121–140, 1986
Volpe JJ: Effect of cocaine use in the fetus. New Engl J Med 327: 399–407, 1992
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Sieber-Blum, M., Ren, Z. Norepinephrine transporter expression and function in noradrenergic cell differentiations. Mol Cell Biochem 212, 61–70 (2000). https://doi.org/10.1023/A:1007100803568
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DOI: https://doi.org/10.1023/A:1007100803568