title: Regulation of Heart Rate in Drosophila via Fragile X Mental Retardation Protein.
abstract: RNA binding proteins play a pivotal role in post-transcriptional gene expression regulation, however little is understood about their role in cardiac function. The Fragile X (FraX) family of RNA binding proteins is most commonly studied in the context of neurological disorders, as mutations in Fragile X Mental Retardation 1 (FMR1) are the leading cause of inherited mental retardation. More recently, alterations in the levels of Fragile X Related 1 protein, FXR1, the predominant FraX member expressed in vertebrate striated muscle, have been linked to structural and functional defects in mice and zebrafish models. FraX proteins are established regulators of translation and are known to regulate specific targets in different tissues. To decipher the direct role of FraX proteins in the heart in vivo, we turned to Drosophila, which harbors a sole, functionally conserved and ubiquitously expressed FraX protein, dFmr1. Using classical loss of function alleles as well as muscle specific RNAi knockdown, we show that Drosophila FMRP, dFmr1, is required for proper heart rate during development. Functional analyses in the context of cardiac-specific dFmr1 knockdown by RNAi demonstrate that dFmr1 is required cell autonomously in cardiac cells for regulating heart rate. Interestingly, these functional defects are not accompanied by any obvious structural abnormalities, suggesting that dFmr1 may regulate a different repertoire of targets in Drosophila than in vertebrates. Taken together, our findings support the hypothesis that dFmr1 protein is essential for proper cardiac function and establish the fly as a new model for studying the role(s) of FraX proteins in the heart.
authors.affiliation: Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, 85724, United States of America.
authors.forename: Stefanie Mares
authors.initials: SM
authors.lastname: Novak
authors.affiliation: Department of Molecular and Cellular Biology The University of Arizona, Tucson, Arizona, 85721, United States of America.
authors.forename: Archi
authors.initials: A
authors.lastname: Joardar
authors.affiliation: Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, 85724, United States of America.
authors.forename: Carol C
authors.initials: CC
authors.lastname: Gregorio
authors.affiliation: Department of Molecular and Cellular Biology The University of Arizona, Tucson, Arizona, 85721, United States of America.
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Zarnescu
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000502:physiology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism*; D006334:Heart Function Tests; D006339:Heart Rate / Q000502:physiology*; D007814:Larva / Q000502:physiology; D009043:Motor Activity; D032383:Myocytes, Cardiac / Q000378:metabolism; D009928:Organ Specificity
chemical_list: D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; C467328:FMR1 protein, Drosophila