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Transcriptional Regulation of Agouti-Related Protein (Agrp) in Transgenic Mice

Departments of Genetics and Pediatrics (C.B.K., A.W.X., G.S.B.), Stanford University School of Medicine, Stanford, California 94305; and Department of Pharmacology (X.-Y.L.), University of Texas Health Science Center, San Antonio, Texas 78229

Address all correspondence and requests for reprints to: Greg Barsh, Beckman Center B271A, Stanford University School of Medicine, Stanford, California 94305-5323. E-mail: gbarsh{at}cmgm.stanford.edu.

Agouti-related protein (Agrp) encodes a hypothalamic neuropeptide that promotes positive energy balance by stimulating food intake and reducing energy expenditure. Agrp expression in the brain is restricted to neurons within the arcuate nucleus of the hypothalamus, and expression levels are elevated as a consequence of food deprivation. We tested a series of bacterial artificial chromosome reporter constructs with varying amounts of sequence flanking the Agrp transcription unit in transgenic mice to identify and refine a region of DNA capable of recapitulating characteristics of Agrp expression. We report that a 42.5-kb region upstream of Agrp, containing three distinct regions that are evolutionarily conserved between mouse and human, is necessary and sufficient to consistently drive reporter expression specifically within AgRP neurons in a fasting-responsive manner. In addition, we demonstrate that this region allows for the stable expression of Cre recombinase in transgenic mice, providing a genetic tool for studying anabolic neural circuits that control energy balance.

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