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The Journal of Neuroscience, December 10, 2008, 28(50):13478-13487; doi:10.1523/JNEUROSCI.2122-08.2008

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Neurobiology of Disease
Mutation of a TADR Protein Leads to Rhodopsin and Gq-Dependent Retinal Degeneration in Drosophila

Lina Ni, Peiyi Guo, Keith Reddig, Mirna Mitra, and Hong-Sheng Li

Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Correspondence should be addressed to Hong-Sheng Li, 364 Plantation Street, LRB 722, Worcester, MA 01605. Email: hong-sheng.li{at}umassmed.edu

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 Gq protein of Rh1 is defective in dissociation from the membrane during light stimulation. Importantly, reduction of Gq level by introducing a hypomorphic allele of G{alpha}q 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 Gq 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.

Key words: retinal degeneration; rhodopsin; G-protein; photoreceptor; Drosophila; GPCR; cation amino acid transporter

Received May 9, 2008; revised Oct. 10, 2008; accepted Nov. 1, 2008.

Correspondence should be addressed to Hong-Sheng Li, 364 Plantation Street, LRB 722, Worcester, MA 01605. Email: hong-sheng.li{at}umassmed.edu






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