Myogenesis represents a critical developmental process that has been conserved throughout the animal kingdom. The mef2 gene, the Drosophila homologue of the vertebrate myocyte specific enhancer factor 2 (MEF2) is expressed in all muscle progenitors and differentiated musculatures. Genetic analysis has shown that mef2 function is essential for differentiation of the three major types of musculature in the Drosophila embryo, body wall muscles, gut musculature, and the heart. Previous studies have revealed that mef2 expression during embryogenesis is controlled by an array of enhancers that are subject to differential inputs. Recent in vivo studies have focused on a particular enhancer which is active at a critical step during myogenesis in pre fusion myoblasts. The goal of the proposed research is to use a multidisciplinary approach to examine the regulatory signals that converge on this enhancer to mediate proper differentiation of somatic (skeletal) myoblasts and normal development of the body wall musculature. The first project entails a molecular genetic screen for isolating novel regulatory factors that bind to essential DNA sequences within the myoblast enhancer. A genetic analysis of the newly identified gene products will be pursued in the second project. In the third project, efforts will be devoted to a genetic and molecular analysis of a new Drosophila mutation that causes a dramatic reduction of mef2 expression specifically in the skeletal muscle lineage but not in visceral or cardiac muscles. Preliminary studies suggest that this mutation disrupts a gene encoding an important regulator of skeletal muscle development, which mediates its function partly through mef2 activation, via the myoblast enhancer under study in projects 1 and 2. The combined molecular and genetic studies of upstream regulators that provide inputs to this myoblast specific mef2 enhancer are expected to yield novel information into a critical control step in somatic myogenesis. The developmental and structural similarities that exist between body wall muscles of the Drosophila embryo and skeletal muscles in vertebrates suggest that many conclusions derived from these proposed studies will provide new insights into the regulatory processes operating during early muscle development in vertebrates. Some of the principles arising from studies in the muscle system may also be applicable to other developmental systems, and thus will potentially contribute to our understanding of other developmental defects in humans.
| Nguyen, Hanh T; Frasch, Manfred (2006) MicroRNAs in muscle differentiation: lessons from Drosophila and beyond. Curr Opin Genet Dev 16:533-9 |
| Duan, H; Skeath, J B; Nguyen, H T (2001) Drosophila Lame duck, a novel member of the Gli superfamily, acts as a key regulator of myogenesis by controlling fusion-competent myoblast development. Development 128:4489-500 |
