Dataset Information

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.

SUBMITTER: Novak SM

PROVIDER: S-EPMC4646288 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Regulation of Heart Rate in Drosophila via Fragile X Mental Retardation Protein.

Novak Stefanie Mares SM Joardar Archi A Gregorio Carol C CC Zarnescu Daniela C DC

PloS one 20151116 11

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 expre ...[more]

PMID: 26571124

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Project description:Fragile X syndrome (FXS), the most common inherited determinant of intellectual disability and autism spectrum disorders, is caused by loss of the fragile X mental retardation 1 (FMR1) gene product (FMRP), an mRNA-binding translational repressor. A number of conserved FMRP targets have been identified in the well-characterized Drosophila FXS disease model, but FMRP is highly pleiotropic in function and the full spectrum of FMRP targets has yet to be revealed. In this study, screens for upregulated neural proteins in Drosophila fmr1 (dfmr1) null mutants reveal strong elevation of two synaptic heparan sulfate proteoglycans (HSPGs): GPI-anchored glypican Dally-like protein (Dlp) and transmembrane Syndecan (Sdc). Our recent work has shown that Dlp and Sdc act as co-receptors regulating extracellular ligands upstream of intracellular signal transduction in multiple trans-synaptic pathways that drive synaptogenesis. Consistently, dfmr1 null synapses exhibit altered WNT signaling, with changes in both Wingless (Wg) ligand abundance and downstream Frizzled-2 (Fz2) receptor C-terminal nuclear import. Similarly, a parallel anterograde signaling ligand, Jelly belly (Jeb), and downstream ERK phosphorylation (dpERK) are depressed at dfmr1 null synapses. In contrast, the retrograde BMP ligand Glass bottom boat (Gbb) and downstream signaling via phosphorylation of the transcription factor MAD (pMAD) seem not to be affected. To determine whether HSPG upregulation is causative for synaptogenic defects, HSPGs were genetically reduced to control levels in the dfmr1 null background. HSPG correction restored both (1) Wg and Jeb trans-synaptic signaling, and (2) synaptic architecture and transmission strength back to wild-type levels. Taken together, these data suggest that FMRP negatively regulates HSPG co-receptors controlling trans-synaptic signaling during synaptogenesis, and that loss of this regulation causes synaptic structure and function defects characterizing the FXS disease state.

Dataset Information

Regulation of Heart Rate in Drosophila via Fragile X Mental Retardation Protein.

Publications

Regulation of Heart Rate in Drosophila via Fragile X Mental Retardation Protein.

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