Mutation of a TADR protein leads to rhodopsin and Gq-dependent retinal degeneration in Drosophila.
The Drosophila photoreceptor is a model system for genetic study of retinal degeneration. Many gene mutations cause fly photoreceptor degeneration, either because of excessive stimulation of the visual transduction (phototransduction) cascade, or through apoptotic pathways that in many cases involve a visual arrestin Arr2. Here we report a gene named tadr (for torn and diminished rhabdomeres), which, when mutated, leads to photoreceptor degeneration through a different mechanism. Degeneration in the tadr mutant is characterized by shrunk and disrupted rhabdomeres, the light sensory organelles of photoreceptor. The TADR protein interacted in vitro with the major light receptor Rh1 rhodopsin, and genetic reduction of the Rh1 level suppressed the tadr mutation-caused degeneration, suggesting the degeneration is Rh1-dependent. Nonetheless, removal of phospholipase C (PLC), a key enzyme in phototransduction, and that of Arr2 failed to inhibit rhabdomeral degeneration in the tadr mutant background. Biochemical analyses revealed that, in the tadr mutant, the G(q) protein of Rh1 is defective in dissociation from the membrane during light stimulation. Importantly, reduction of G(q) level by introducing a hypomorphic allele of G(alphaq) gene greatly inhibited the tadr degeneration phenotype. These results may suggest that loss of a potential TADR-Rh1 interaction leads to an abnormality in the G(q) signaling, which in turn triggers rhabdomeral degeneration independent of the PLC phototransduction cascade. We propose that TADR-like proteins may also protect photoreceptors from degeneration in mammals including humans.
Ni
Lina
L
Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Guo
Peiyi
P
Reddig
Keith
K
Mitra
Mirna
M
Li
Hong-Sheng
HS
D000818:Animals; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics*; D004596:Electroretinography; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D017344:Genes, Insect; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D018408:Patch-Clamp Techniques; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012243:Rhodopsin / Q000378:metabolism*
D029721:Drosophila Proteins; D012243:Rhodopsin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11