By Madeline Brunt

Faculty Mentor: Dr. Ginny Morriss

Abstract

Myotonic dystrophy type 1 (DM1) is an inherited multisystem disorder that causes severe muscle wasting. DM1 results from CTG-repeat expansions in the untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. While the cause of DMl is known, the underlying mechanism behind DM1 muscle wasting is not fully understood. Previous research using a mouse model of DMl with severe muscle wasting showed deregulated PDGFRß signaling. PDGFRß is a receptor that regulates cell growth, survival, and differentiation. Our lab is evaluating the role of the Drosophila melanogaster PDGFR ortholog, pvr, in muscle maintenance and the progression of DM1 phenotypes. We are using the Gal4/UAS system in Drosophila to knockdown pvr expression via RNAi (pvr-RNAi) in the presence of expanded CUG-repeat RNA (CUGexp). These models will allow assessment of the role of pvr signaling in the progression of DM1 phenotypes. We will knockdown pvr in both the control (UAS-CUG20) and DM1 fly model (UAS-CUG250) using Mef2-Gal4 to drive skeletal muscle-specific expression of both CUGexp repeats and the modifier. We will measure climbing velocity (mm/second) and flight capability (landing height in cm) to assess muscle function in these flies. Representative samples will be prepared for histological analysis to measure muscle atrophy. RT-qPCR of RNA isolated from the thoraces will allow evaluation of expression levels of pur to test the efficacy of knockdown, as well as Pvr signaling downstream targets hid, dpp, thor, and myc. We will analyze levels of activated Pvr protein in all samples via western blot. Matings to generate appropriate genotypes are currently underway. We expect this research will shed light on the requirement of pvr signaling for proper skeletal muscle development and function in flies and in the progression of DM1.