Signaling through the Dystrophin Glycoprotein Complex affects the stress-dependent transcriptome in Drosophila

Abstract

The Dystrophin Glycoprotein Complex (DGC) is a cell membrane-spanning complex that links the extracellular matrix with the intracellular cytoskeleton. Deficiencies in the DGC in humans cause muscular dystrophies (MDs), a group of inherited, incurable disorders associated with heterogeneous muscle, brain, and eye anomalies. To advance disease diagnostics and develop new treatment strategies, it is essential to understand the genetic pathways that are perturbed by DGC mutations and the mechanisms underlying these pathologies. Stresses such as nutrient deprivation and aging cause a reduction of muscle mass can be exacerbated by a reduced content of the DGC in membranes, whose integrity is vital for muscle health and function. This illustrates that the DGC plays a role in stress-response pathways. Therefore, it is important to investigate the influence of stress not only on healthy individuals but also on the wellbeing of MD patients. Moreover, the DGC has also emerged as an integral component in multiple signaling pathways, demonstrating an important yet poorly understood connection between intercellular forces and regulation of gene expression and illustrating the importance of understanding DGC-related transcriptional effects. Here, we utilize a Drosophila model to investigate the transcriptomic changes in mutants of four different DGC components under unstressed, temperature-stressed, and starvation-stressed conditions. Our analysis reveals a group of genes that exhibit DGC-dependent gene regulation. We identify large groups of genes that are differentially regulated in response to either temperature or starvation stress. Importantly, we also identify groups of genes with expression patterns dependent on the DGC signaling pathway for a proper stress response. This work reveals a novel function of the DGC in stress-response signaling. The view of the DGC as a regulatory unit involved in the stress response will give new insights into the etiology of symptoms of MDs and possible directions of symptomatic treatment and relief, and it will ultimately aid in a better understanding of DGC signaling and regulation under normal and stress conditions.