Muscular dystrophies are a group of inherited neuromuscular disorders that share the same basic phenotype of progressive loss of muscle integrity. Many muscular dystrophies are caused by defects in a specialized cell adhesion complex called the Dystrophin Glycoprotein Complex (DGC). It has become evident that this complex plays a central role in muscle integrity and forms a mechanical link from the actin cytoskeleton to the extracellular matrix (ECM). The core DGC is composed of a transmembrane component, Dystroglycan (Dg), which associates with the ECM protein, Laminin and the cytoplasmic protein Dystrophin which binds Actin (reviewed in 
Many lines of evidence confirm that maintaining the structural link from the extracellular matrix to the actin cytoskeleton is crucial in preventing many forms of muscular dystrophy. Mutations that disrupt any component of this structural link results in a variety of muscular dystrophies like Duchenne's, Becker's, Muscle-eye-brain disease, Walker-Warburg syndrome, congenital muscular dystrophies 1C and 1D as well as limb girdle muscular dystrophy 2I. These diseases share the common symptoms of skeletal muscle degeneration, cardiomyopathy, as well as a reduced life span for afflicted individuals 
Additionally, alterations which reduce the affinity of components of the DGC lead to congenital muscular dystrophies like Fukuyama's which, aside from muscular defects, also are associated with aberrant neuronal migrations that lead to mental retardation, epilepsy, as well as abnormal eye development. The use of animal model systems has led to the clarification of the roles of specific gene products in maintaining muscle integrity and function (reviewed in 
), however, the regulation of this complex is largely unknown.
Initial characterization of the DGC in Drosophila
has determined that components studied so far possess similar roles in muscle integrity and neuronal migration in flies as in humans (, 
). These abnormalities include age dependent muscle degeneration, reduced mobility, defects in eye development as manifested by altered photoreceptor axon pathfinding, and a shorter life span. Additionally, mutations in Dys
affect cell polarity in the Drosophila
germ line as both the follicular cell epithelium and the oocyte are disrupted 
. Recently, a reduced lifespan in Drosophila
, as well as heart and muscle abnormalities, have been reported in mutants of another component of the DGC, δ-
. In addition, heart and eye phenotypes have been observed in Drosophila Dys
Muscle Phenotypes of Dys Mutants.
The similar defects in both flies and humans make Drosophila
an attractive model for further studies on clarifying the role of the DGC. Such studies may reveal novel components that may likely have counterparts in humans. Additionally, since very little is known about how the DGC is regulated insights may be gained on this heretofore unknown process. More recently, transmembrane signaling has been implicated in the function of the DGC. The C-terminus of Dystroglycan, in addition to having, EF and WW domain binding sites, also possesses SH2 and SH3 domain binding sites. These known protein-protein interaction motifs support the idea that Dystroglycan is a signaling receptor in addition to its known role as a conduit between the ECM and the cytoskeleton. Changes in MAPK kinase and GTPase signaling have also been observed when the DGC is perturbed 
. Recent work has shown that specific sets of domains are critical in the function of Drosophila
In the present work, we have used the genetic tractability of Drosophila
to search for novel components of the DGC, as well as components that may be involved in its signaling and regulation. Such a search is straightforward because in addition to the muscle degeneration and photoreceptor axon pathfinding defects, mutations in dystrophin
cause a visible phenotype manifested as alterations in the fly wing, particularly the posterior crossvein (, 
). Since this is an easily score-able, highly penetrant phenotype we undertook a dominant modifier screen approach and looked for flies that showed either a suppression of the crossvein phenotype or a noticeably altered crossvein. Importantly, crossvein development has been previously shown to require EGFR, TGF-β and Notch pathway activities and is therefore a sensitive place to observe potential interactions of the DGC with these signaling pathways 
. In addition, hemocyte migration is shown to correlate with the crossvein development 
. Therefore genes involved in correct migration processes might also be obtained by this approach. We screened P-element lethal as well as deficiency collections for interactors in addition to performing a classical ethylmethanesulfonate (EMS) screen for dominant modifiers.
Dys and Dg are Required for Proper Wing Vein Formation and Interact in the Process.
Here we report that in using these screening strategies we have found modifiers that belong to six different functional groups. We have found genes involved in muscle development, neuronal/cell migration and motor function as well as cytoskeletal components and components of the TGF-β, EGFR and Notch pathways. A common theme among many of these interactors and Dg-Dys complex is their involvement in the cytoskeletal rearrangements controlled by extracellular cues.