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

Abstract

Abstract-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 Ⅲ heart rate Ⅲ cardiac failure Ⅲ aging Ⅲ muscle A lthough much effort has gone into defining developmental pathways, many of the mechanistic aspects of regulatory processes occurring during tissue specialization and organogenesis remain to be elucidated. The homeoboxcontaining gene even skipped (eve) is involved in several such aspects of tissue specialization. It was first identified in Drosophila as a segmentation gene. 1 Later during development, eve is expressed in the nervous system and in dorsal muscle progenitors and pericardial cells. 2 Regulatory elements for each of these aspects of the pattern were localized, 3,4 and a transgenic copy of the eve gene was shown to fully supply eve function. 3 Specific repressor domains of Eve were identified in cultured cell assays 5,6 and subsequently shown to interact functionally with corepressors. [7][8][9] eve is expressed in, and required for the formation of, a subset of dorsal muscle and pericardial (PC) cells. 10 -12 In the developing mesoderm, early progenitors in the cardiogenic region express eve in segmentally repeated clusters that later differentiate into eve-positive pericardial cells (EPCs) and dorsal acute muscle 1 (DA1). 2 A transgene was generated that fully rescues the phenotype of eve null mutants in all other tissues, but gives no detectable expression or function in the mesoderm, and resulting embryos were shown to develop mesodermal-specific defec...

Defective Decapentaplegic Signaling Results in Heart Overgrowth and Reduced Cardiac Output in Drosophila

“…These studies also showed that pericardial cells secrete proteins into the hemolymph, suggesting that one pericardial cell function may be to provide short-or long-range signals. Consistent with this, reducing pericardial cell number reduces heart rate and increases the cardiac failure rate, suggesting that pericardial cells influence the development of cardiac cells (Fujioka et al 2005).…”

3D chromatin interactions organize Yan chromatin occupancy and repression at the even-skipped locus

“…Precise regulation of eve expression in the cardiogenic mesoderm is essential for acquisition of heart cell identity and ultimately for cardiac function (Fujioka et al 2005;Johnson et al 2007). Consistent with this, the elevated expression of Eve DD1 -YFP reflected in part an increase in the number of Eve-positive mesodermal cells specified ( Fig.…”

Neprilysin 4, a novel endopeptidase fromDrosophila melanogaster, displays distinct substrate specificities and exceptional solubility states

“…Shortly after, DO2 loses Eve expression, whereas the EPCs remain Eve positive. One cell from the second Eve cluster (cluster 15) divides to yield the DA1 muscle founder (that maintains Eve expression) and a second cell that is assumed to die (Alvarez et al, 2003;Carmena et al, 1998;Fujioka et al, 2005;Han and Bodmer, 2003). Besides DA1, Krüppel additionally labels a second muscle founder within the dorsal mesoderm, which is the DO1 founder (Ruiz-Gómez et al, 1997).…”