Degenerative diseases of the eye, specifically outer retinal dystrophies, are a major cause of incurable blindness. One gene that may play a role in retinopathy is the basigin gene (aka EMMPRIN in humans). Basigin is a member of a gene family that encodes cell surface IgG proteins that are implicated in cellular interactions. We are using Drosophila as a model system to study basigin's role in basic visual system cell biology and visual system function. We have identified several basigin functions in the visual system using flies, many of which are co-incident with functions described in vertebrates. For example, basigin mutant mice show abnormal electroretinograms (ERGs) as do mosaic flies in which basigin function is mutant in the eye (Clamp et al., 2003;Curtin et al., 2007). Basigin mutant mice show altered photoreceptor (PC) cell structure (Ochreitor et al., 2001). Drosophila basigin is required for normal photoreceptor cell structure (Curtin et al., 2005). Basigin has been implicated in neuron-glia interaction in dissociated cells from the avian visual system (Fadool and Linser, 1993). Drosophila basigin is necessary for neuron-glia interactions in the optic lamina (Curtin et al., 2007). All these co-incidences argue strongly that what we learn about basigin molecular function in the Drosophila retina will help us understand its function in the mammalian retina. Lastly, both fly and mouse basigin can rescue the defects seen in the visual system of mosaic basigin flies showing that mammalian basigin can make similar molecular contacts as Drosophila basigin (Curtin et al., 2005, 2007). Our main goal is to understand the molecular mechanisms by which basigin acts to promote normal visual system structure and function. Our preliminary data show that basigin forms protein complexes. We are using a yeast two-hybrid assay designed to detect protein interactions at the membrane to identify putative basigin-interacting proteins and the genes that encode them. We will use genetic/ functional studies and biochemistry to identify the functional significance of these protein interactions as well as exploring the significance of specific basigin protein modifications for basigin cellular functions. The ability to specifically manipulate the genetic make-up of the eye independent of the rest of the animal provides us with an exceptional system to study the molecular function of basigin and the genes for basigin interacting proteins.
The proposed studies have relevance to human health by exploring the molecular role of basigin/EMMPRIN in the maintenance and function of the visual system. The project's main aim is to identify basigin-interacting proteins in the eye and to analyze the genes that code for these proteins so that we can better understand how basigin affects visual system development and function.
