We are interested in a deeper understanding of the components and regulation of the phototransduction cascade and learning how perturbations in photoreceptor cell physiology lead to various forms of retinal degeneration. We use the Drosophila visual system to examine these broad questions. Drosophila is amenable to molecular, electrophysiological, and genetic approaches to identify molecules and to study in vivo the protein relationships in biochemical pathways. Because many invertebrate visual transduction proteins have vertebrate homologs, both cascades may function in an analogous manner. Thus, the identification of molecules and mechanisms in Drosophila may clarify the vertebrate visual transduction pathway. Many visual transduction molecules exhibit retinal degeneration when altered in either invertebrates or vertebrates. Therefore, studying the role of these molecules in visual transduction will elucidate the mechanisms leading to degeneration. We will extend our analysis of Drosophila retinal degeneration-B (rdgB), which exhibits light-dependent degeneration of photoreceptors. The rdgB protein is a novel phosphatidylinositol transfer protein (PI-TP) required in the visual transduction cascade. One defined role for PI-TPs is regulation of vesicular transport. Immunolocalization of the rdgB protein near the cytosolic face of the rhabdomeres is consistent with the protein functioning in vesicular transport from a trans-Golgi compartment to the rhabdomeres. The rdgB polyclonal antiserum stains vertebrate rod inner segments, suggesting that a vertebrate """"""""photoreceptor"""""""" homolog exists. Detailed analysis of the Drosophila molecule and identification of the vertebrate homolog could elucidate aspects of rod outer disc assembly and possibly a novel form of retinal degeneration. The dgq gene encodes two Drosophila photoreceptor-specific G-protein a subunits, DGq1 and DGq2. We demonstrated genetically and biochemically that DGq1 is involved in the light-activated pathway. Further analyses will reveal what is DGq1 's effector molecule and the role of DGq2 in the phototransduction cascade. In addition, an analogous dominant mutation in both DGq1 and transducin leads to an abnormal adaptation response in Drosophila and mouse, respectively. Therefore, further genetic and molecular analyses of DGq1 may elucidate a common adaptation mechanism in both vertebrates and invertebrates.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY008058-08
Application #
2459113
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1989-09-01
Project End
1998-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Notre Dame
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
Elagin, V A; Elagina, R B; Doro, C J et al. (2000) Cloning and tissue localization of a novel zebrafish RdgB homolog that lacks a phospholipid transfer domain. Vis Neurosci 17:303-11
Paetkau, D W; Elagin, V A; Sendi, L M et al. (1999) Isolation and characterization of Drosophila retinal degeneration B suppressors. Genetics 151:713-24
Lu, C; Vihtelic, T S; Hyde, D R et al. (1999) A neuronal-specific mammalian homolog of the Drosophila retinal degeneration B gene with expression restricted to the retina and dentate gyrus. J Neurosci 19:7317-25
Chang, J T; Milligan, S; Li, Y et al. (1997) Mammalian homolog of Drosophila retinal degeneration B rescues the mutant fly phenotype. J Neurosci 17:5881-90
Milligan, S C; Alb Jr, J G; Elagina, R B et al. (1997) The phosphatidylinositol transfer protein domain of Drosophila retinal degeneration B protein is essential for photoreceptor cell survival and recovery from light stimulation. J Cell Biol 139:351-63
Zars, T; Hyde, D R (1996) rdgE: a novel retinal degeneration mutation in Drosophila melanogaster. Genetics 144:127-38
Shah, S; Hyde, D R (1995) Two Drosophila genes that encode the alph and beta subunits of the brain soluble guanylyl cyclase. J Biol Chem 270:15368-76
Lee, Y J; Shah, S; Suzuki, E et al. (1994) The Drosophila dgq gene encodes a G alpha protein that mediates phototransduction. Neuron 13:1143-57
Vihtelic, T S; Goebl, M; Milligan, S et al. (1993) Localization of Drosophila retinal degeneration B, a membrane-associated phosphatidylinositol transfer protein. J Cell Biol 122:1013-22
Vihtelic, T S; Hyde, D R; O'Tousa, J E (1991) Isolation and characterization of the Drosophila retinal degeneration B (rdgB) gene. Genetics 127:761-8

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