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J Biol Chem, Vol. 275, Issue 13, 9186-9192, March 31, 2000

Regulation by Neurotransmitter Receptors of Serotonergic or Catecholaminergic Neuronal Cell Differentiation*

Sophie Mouillet-RichardDagger §, Vincent Mutel, Sylvain LoricDagger , Claire TournoisDagger ||, Jean-Marie Launay||, and Odile KellermannDagger **

From the Dagger  Différenciation Cellulaire, CNRS URA 1960, Institut Pasteur, 75724 Paris Cedex 15 France,  Pharma Research Department, Hoffmann-La-Roche A.G., Basel 40002, Switzerland, and || CR Claude Bernard, Pathologie Expérimentale et Communications Cellulaires, IFR 6, Service de Biochimie, Hôpital Lariboisière, 75010 Paris, France

The murine F9-derived 1C11 clone exhibits a stable epithelial morphology, expresses nestin, an early neuroectodermal marker, and expresses genes involved in neuroectodermal cell fate. Upon appropriate induction, 100% of 1C11 precursor cells develop neurite extensions and acquire neuronal markers (N-CAM, synaptophysin, gamma gamma -enolase, and neurofilament) as well as the general functions of either serotonergic (1C11*/5HT) (5HT, 5-hydroxytryptamine) or noradrenergic (1C11**/NE) (NE, norepinephrine) neurons. The two programs are shown to be mutually exclusive. 1C11 thus behaves as a neuroepithelial cell line with a dual bioaminergic fate. 1C11*/5HT cells implement a functional 5-HT transporter and thereby a complete serotonergic phenotype within 4 days, whereas 5-HT1B/D, 5-HT2B, and 5-HT2A receptors are sequentially induced. The accurate time schedule of catecholaminergic differentiation was defined. Catecholamine synthesis, storage, and catabolism are acquired within 4 days; the noradrenergic phenotype is complete at day 12 and includes a functional norepinephrine transporter and an alpha 1D-adrenoreceptor (day 8). The time-dependent onset of neurotransmitter-associated functions proper to either program is similar to in vivo observations. Along each pathway, the selective induction of serotonergic or adrenergic receptors is shown to be an essential part of the differentiation program, since they promote an autoregulation of the corresponding phenotype.

* This study was supported by CNRS Grants URA 1960 and ARC 6668 and the Ligue Nationale contre le Cancer.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ This author is on leave of absence from the Ecole Nationale du Génie Rural des Eaux et des Forêts.

** To whom correspondence should be addressed: Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15 France. Tel.: 33145688465; Fax: 33140613194; E-mail: okellerm@pasteur.fr.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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