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J. Biol. Chem., Vol. 281, Issue 40, 29753-29761, October 6, 2006

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Regulation of Hypocretin (Orexin) Expression in Embryonic Zebrafish^*

Juliette H. Faraco¹, Lior Appelbaum¹, Wilfredo Marin, Stephanie E. Gaus, Philippe Mourrain^¶, and Emmanuel Mignot²

From the Stanford University Center for Narcolepsy, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, the Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, and ^¶INSERM, U784, 75230 Paris, France

Hypocretins/orexins are neuropeptides involved in the regulation of sleep and energy balance in mammals. Conservation of gene sequence, hypothalamic localization of cell bodies, and projection patterns in adult zebrafish suggest that the architecture and function of the hypocretin system are conserved in fish. We report on the complete genomic structure of the zebrafish and Tetraodon hypocretin genes and the complete predicted hypocretin protein sequences from five teleosts. Using whole mount in situ hybridization, we have traced the development of hypocretin cells in zebrafish from onset of expression at 22 h post-fertilization through the first week of development. Promoter elements of similar size from zebrafish and Tetraodon were capable of driving efficient and specific expression of enhanced green fluorescent protein in developing zebrafish embryos, thus defining a minimal promoter region able to accurately mimic the native hypocretin pattern. This enhanced green fluorescent protein expression also revealed a complex pattern of projections within the hypothalamus, to the midbrain, and to the spinal cord. To further analyze the promoter, a series of deletion and substitution constructs were injected into embryos, and resulting promoter activity was monitored in the first week of development. A critical region of 250 base pairs was identified containing a core 13-base pair element essential for hypocretin expression.

Received for publication, June 16, 2006 , and in revised form, July 21, 2006.

^* This work was supported by the MacKnight Foundation and the Howard Hughes Medical Institute. 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 These authors contributed equally to this work.

² Howard Hughes Medical Institute Investigator. To whom correspondence should be addressed: Center for Narcolepsy Research, 701B Welch Road, Palo Alto, CA 94304-5742. Tel.: 650-725-6517; Fax: 650-725-725-4913; E-mail: mignot{at}stanford.edu.

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