Modeling Human MEGF10 Myopathy in Drosophila melanogaster

Abstract

Mutations in MEGF10 underlie a rare congenital muscle disease in humans. MEGF10 is a single transmembrane receptor that is expressed in skeletal muscles as well as in CNS glial cells, in both mammals and Drosophila. Expression of Drpr, the Drosophila homolog of human MEGF10, in fly muscles offers a unique opportunity to probe the role of this receptor in muscle physiology and disease. We have shown that loss‐of‐function mutations in Drpr lead to muscle alterations that recapitulate important features of the human disease. To complement this genetic tool, we have now developed a MEGF10 gain‐of‐function model in Drosophila. In the present study we show that ubiquitous or skeletal muscle‐specific overexpression of either Drosophila Drpr, or mouse MEGF10, in flies leads to decreased viability, whereas heart or glia‐specific overexpression does not. Preliminary analysis carried out by overexpressing the different mammalian or fly MEGF10 receptor orthologs, suggests an important role for the conserved extracellular EMI domain of the protein, to ensure normal function in muscle. Our complementary MEGF10 loss of function/gain of function Drosophila models enable us to begin dissecting the conserved functional pathways regulated by this protein in muscle cells. Together our studies indicate that narrow alterations in the levels of MEGF10 expression may impair normal muscle physiology in vivo. This study was funded by NIHgrant R01 NS080929 (PBK and ID).