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J. Biol. Chem., Vol. 283, Issue 24, 16860-16867, June 13, 2008

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Regulation of the Noradrenaline Neurotransmitter Phenotype by the Transcription Factor AP-2β^*

Seok Jong Hong, Thomas Lardaro, Myung Sook Oh¹, Youngbuhm Huh, Yunmin Ding, Un Jung Kang, Jutta Kirfel^¶, Reinhard Buettner^¶, and Kwang-Soo Kim²

From the Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, the Department of Neurology and Neurobiology, Pharmacology & Physiology, University of Chicago, Chicago, Illinois 60637, and the ^¶Institute of Pathology, University Hospital Bonn, D-53127 Bonn, Germany

AP-2 family transcription factors are essential for development and morphogenesis of diverse tissues and organs, but their precise roles in specification of neural crest stem cell (NCSC)-derived cell types have not been determined. Among three members known to be expressed in the NCSC (i.e. AP-2, AP-2β, and AP-2), we found that only AP-2β is predominantly expressed in the sympathetic ganglia of developing mouse embryos, supporting its role in sympathetic development. Indeed, AP-2β null mice expressed significantly reduced levels of both noradrenaline (NA) and NA-synthesizing dopamine β-hydroxylase in the peripheral nervous system. Strikingly, we also found that NA neuron development was significantly compromised in the locus coeruleus as well. Pharmacological treatment with an NA intermediate during pregnancy significantly rescues the neonatal lethality of AP-2β^-/- mice, indicating that NA deficiency is one of the main causes for lethality found in AP-2β^-/- mice. We also showed that forced expression of AP-2β, but not other AP-2 factors, in NCSC favors their differentiation into NA neurons. In summary, we propose that AP-2β plays critical and distinctive roles in the NA phenotype specification in both the peripheral and central nervous system during development.

Received for publication, November 6, 2007 , and in revised form, February 27, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants MH48866 and DC006501. This work was also supported by an International Grant from the Brain Research Center funded by the Korean Ministry of Science and Technology (to K. S. K.), by Korea Research Foundation Grant KRF-2006-214-E00037 (to M. S. O.), and by a grant from the Deutsche Forschungsgemeinschaftand (to R. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and supplemental Figs. S1-S3.

¹ Present address: Dept. of Medicinal Herbology, 312 College of Pharmacy, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Korea.

² To whom correspondence should be addressed: Molecular Neurobiology Laboratory, MRC215, McLean Hospital, Harvard Medical School, 115 Mill St., Belmont, MA 02478. Tel.: 617-855-2024; Fax: 617-855-3479; E-mail: kskim{at}mclean.harvard.edu.

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