Muscular dystrophies are a group of diseases that are often caused by loss-of-function mutations affecting the dystrophin glycoprotein complex (DGC). The common feature of the diseases is muscle degeneration, which is often associated with mental retardation and various retinal defects, including ones of synaptic transmission. However, the mechanisms of the disease remain largely unknown, especially those in the central nervous system. I have focused on dystroglycan (DG), the transmembrane protein in the DGC that links the cytoskeleton to the extracellular matrix and is essential for muscle survival and brain development. I have used proteomics and Drosophila genetics to study DG function in the brain and retina.Using proteomics I found that beta-DG is directly associated with the GTPase dynamin 1 in the retina and in the brain together with alpha-DG and Grb2, and immunohistochemically beta-DG was colocalized with dynamin 1 in the outer plexiform layer where photoreceptor terminals are localized. Moreover, loss of DG in differentiated DG-null embryonic stem cells significantly increases dynamin-mediated transferrin-uptake and re-expression of DG in null cells by infection with an adenovirus containing DG reduced transferrin uptake to levels seen in wild-type cells. This result implies that one of mechanisms in muscular dystrophy might be the altered synaptic vesicle endocytosis, especially in the retina where synaptic transmission defect has been known for decades.Muscular dystrophies show not only impaired retinal synaptic transmission and several DG-related congenital muscular dystrophies also display retinal structural defects. To further understand the roles of DG in the retina, I used Drosophila eye as a model and demonstrated for the first time that DG is required cell-autonomously for photoreceptor morphogenesis in the developing visual system. Deficiency of DG in the eye causes severe disruption of retinal structure, aberrant lens formation and abolition of electroretinogram in the adult fly eye. These adult defects appear derived from autonomous photoreceptor cell (PRC) defects in the early pupa including size arrest, loss of polarity and progressive degeneration. All defects in the eye, however, can be reversed by re-expression of wild type DG in DG-deficient PRCs, suggesting DG functions cell-autonomously in PRCs and non-autonomously for lens. In the 3rd instar larvae DG is present in the apical tips and the basal membranes of PRCs, two polarized locations opposing the extracellular matrix. At the pupal stage it continues to mainly distribute at the apical rhabdomere and basal membrane of PRCs. Over-expression of DG leads to larger ommatidia but the PRC number remains unchanged, suggesting that DG is both necessary for and sufficient to promote PRC expansion. By rescue experiments, I demonstrated that the extracellular DG alone could not rescue DG-deficient eye defects, whereas the intracellular DG can substantially ameliorate PRC degeneration and structural defects while some PRCs remain disorganized, a sign of disrupted PRC planar polarity in absence of the extracellular DG. Therefore, our data suggest that the degeneration and planar polarity disruption in DG-deficient PRCs are two independent processes that appear to require the respective function of intracellular and extracellular DG. In summary, our experiments demonstrated several novel findings and provided the basis for future investigations on DG function and the molecular mechanisms of nervous system defects in muscular dystrophies
