Dg-Dys-Syn1 signaling in Drosophila regulates the microRNA profile.

ABSTRACT

BACKGROUND: The Dystrophin Glycoprotein Complex (DGC) is at the center of significant inheritable diseases, such as muscular dystrophies that can be fatal and impair neuronal function in addition to muscle degeneration. Recent evidence has shown that it can control cellular homeostasis and work via Dystrophin signaling to regulate microRNA gene expression which implies that disease phenotypes hide an entourage of regulatory and homeostatic anomalies. Uncovering these hidden processes could shed new light on the importance of proper DGC function for an organism's overall welfare and bring forth new ideas for treatments. RESULTS: To better understand a role for the DGC in these processes, we used the genetically advantageous Drosophila muscular dystrophy model to conduct a whole animal microarray screen. Since we have recently found that dystrophic symptoms can be caused by stress even in wild type animals and are enhanced in mutants, we screened stressed animals for microRNA misregulation as well. We were able to define microRNAs misregulated due to stress and/or dystrophy. Our results support the hypothesis that there is a Dystrophin and Dystroglycan dependent circuitry of processes linking stress response, dystrophic conditions and cellular signaling and that microRNAs play an important role in this network. Verification of a subset of our results was conducted via q-PCR and revealed that miR-956, miR-980 and miR-252 are regulated via a Dystroglycan-Dystrophin-Syntrophin dependent pathway. CONCLUSIONS: The results presented in this study support the hypothesis that there is a Dystrophin and Dystroglycan dependent circuitry of processes that includes regulation of microRNAs. Dystrophin signaling has already been found to occur in mammalian musculature; however, our data reveals that this regulation is evolutionarily conserved and also present in at least neuronal tissues. Our data imply that Dystroglycan-Dystrophin-Syntrophin signaling through control of multiple microRNAs is involved in highly managed regulation of gene expression required to adapt cellular homeostasis that is compromised under stress and dystrophic conditions.