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(Circulation Research. 2005;97:1108.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Embryonic even skipped–Dependent Muscle and Heart Cell Fates Are Required for Normal Adult Activity, Heart Function, and Lifespan

Miki Fujioka^*, Robert J. Wessells^*, Zhe Han, Jiandong Liu, Kerry Fitzgerald, Galina L. Yusibova, Monica Zamora, Pilar Ruiz-Lozano, Rolf Bodmer, James B. Jaynes

From the Department of Microbiology and Immunology (M.F., G.L.Y., J.B.J.), Thomas Jefferson University, Philadelphia, Pa; The Burnham Institute (R.J.W., J.L., K.F., M.Z., P.R.-L., R.B.), La Jolla, Calif; and the Department of Molecular Biology (Z.H.), University of Texas Southwestern Medical Center, Dallas.

Correspondence to James B. Jaynes, Department of Microbiology and Immunology, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107. E-mail jaynes{at}mail.jci.tju.edu; or Rolf Bodmer, The Burnham Institute, 10901 North Torrey Pines Rd, La Jolla, CA 92037. E-mail rolf@burnham.org.

The Drosophila pair-rule gene even skipped (eve) is required for embryonic segmentation and later in specific cell lineages in both the nervous system and the mesoderm. We previously generated eve mesoderm-specific mutants by combining an eve null mutant with a rescuing transgene that includes the entire locus, but with the mesodermal enhancer removed. This allowed us to analyze in detail the defects that result from a precisely targeted elimination of mesodermal eve expression in the context of an otherwise normal embryo. Absence of mesodermal eve causes a highly selective loss of the entire eve-expressing lineage in this germ layer, including those progeny that do not continue to express eve, suggesting that mesodermal eve precursor specification is not implemented. Despite the resulting absence of a subset of muscles and pericardial cells, mesoderm-specific eve mutants survive to fertile adulthood, providing an opportunity to examine the effects of these developmental abnormalities on adult fitness and heart function. We find that in these mutants, flying ability, myocardial performance under normal and stressed conditions, and lifespan are severely reduced. These data imply a nonautonomous role of the affected pericardial cells and body wall muscles in developing and/or maintaining cardiac performance and possibly other functions contributing to normal lifespan. Given the similarities of molecular-genetic control between Drosophila and vertebrates, these findings suggest that peri/epicardial influences may well be important for proper myocardial function.

Key Words: cardiac development • heart rate • cardiac failure • aging • muscle

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