The ATP-sensitive potassium (KATP) channel-encoded dSUR gene is required for Drosophila heart function and is regulated by tinman.
The homeobox transcription factor Tinman plays an important role in the initiation of heart development. Later functions of Tinman, including the target genes involved in cardiac physiology, are less well studied. We focused on the dSUR gene, which encodes an ATP-binding cassette transmembrane protein that is expressed in the heart. Mammalian SUR genes are associated with K(ATP) (ATP-sensitive potassium) channels, which are involved in metabolic homeostasis. We provide experimental evidence that Tinman directly regulates dSUR expression in the developing heart. We identified a cis-regulatory element in the first intron of dSUR, which contains Tinman consensus binding sites and is sufficient for faithful dSUR expression in the fly's myocardium. Site-directed mutagenesis of this element shows that these Tinman sites are critical to dSUR expression, and further genetic manipulations suggest that the GATA transcription factor Pannier is synergistically involved in cardiac-restricted dSUR expression in vivo. Physiological analysis of dSUR knock-down flies supports the idea that dSUR plays a protective role against hypoxic stress and pacing-induced heart failure. Because dSUR expression dramatically decreases with age, it is likely to be a factor involved in the cardiac aging phenotype of Drosophila. dSUR provides a model for addressing how embryonic regulators of myocardial cell commitment can contribute to the establishment and maintenance of cardiac performance.
Akasaka
Takeshi
T
Del E. Webb Center for Neurosciences and Aging, The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Klinedinst
Susan
S
Ocorr
Karen
K
Bustamante
Erika L
EL
Kim
Seung K
SK
Bodmer
Rolf
R
D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000375:Aging; D000818:Animals; D001665:Binding Sites; D029721:Drosophila Proteins / Q000502:physiology*; D004331:Drosophila melanogaster; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D000860:Hypoxia; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism; D010641:Phenotype; D015221:Potassium Channels / Q000737:chemistry; D012097:Repressor Proteins / Q000502:physiology*; D064233:Sulfonylurea Receptors; D015534:Trans-Activators / Q000502:physiology*
D018528:ATP-Binding Cassette Transporters; D029721:Drosophila Proteins; D015221:Potassium Channels; D012097:Repressor Proteins; D064233:Sulfonylurea Receptors; D015534:Trans-Activators; C102933:tin protein, Drosophila