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J. Biol. Chem., Vol. 281, Issue 44, 33749-33760, November 3, 2006

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µ- and -Opioids Induce the Differentiation of Embryonic Stem Cells to Neural Progenitors^*

Eunhae Kim, Amy L. Clark, Alexi Kiss, Jason W. Hahn, Robin Wesselschmidt, Carmine J. Coscia, and Mariana M. Belcheva¹

From the E. A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri 63104 and Primogenix, Inc., Los Angeles, California 90033

Growth factors, hormones, and neurotransmitters have been implicated in the regulation of stem cell fate. Since various neural precursors express functional neurotransmitter receptors, which include G protein-coupled receptors, it is anticipated that they are involved in cell fate decisions. We detected µ-opioid receptor (MOR-1) and -opioid receptor (KOR-1) expression and immunoreactivity in embryonic stem (ES) cells and in retinoic acid-induced ES cell-derived, nestin-positive, neural progenitors. Moreover, these G protein-coupled receptors are functional, since [D-Ala²,MePhe⁴,Gly-ol⁵]enkephalin, a MOR-selective agonist, and U69,593, a KOR-selective agonist, induce a sustained activation of extracellular signal-regulated kinase (ERK) signaling throughout a 24-h treatment period in undifferentiated, self-renewing ES cells. Both opioids promote limited proliferation of undifferentiated ES cells via the ERK/MAP kinase signaling pathway. Importantly, biochemical and immunofluorescence data suggest that [D-Ala²,MePhe⁴,Gly-ol⁵]enkephalin and U69,593 divert ES cells from self-renewal and coax the cells to differentiate. In retinoic acid-differentiated ES cells, opioid-induced signaling features a biphasic ERK activation profile and an opioid-induced, ERK-independent inhibition of proliferation in these neural progenitors. Collectively, the data suggest that opioids may have opposite effects on ES cell self-renewal and ES cell differentiation and that ERK activation is only required by the latter. Finally, opioid modulation of ERK activity may play an important role in ES cell fate decisions by directing the cells to specific lineages.

Received for publication, April 21, 2006 , and in revised form, August 24, 2006.

^* This work was supported in part by National Institutes of Health Grant DA-05412 (to C. J. C.) and by the American Parapalegia Society and the Pediatrics Research Institute of St. Louis University School of Medicine (to M. M. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO, 63104. Tel.: 314-977-9256; Fax: 314-977-9205; E-mail: beltchem{at}slu.edu.

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