Human Molecular Genetics Advance Access originally published online on August 12, 2008
Human Molecular Genetics 2008 17(22):3487-3501; doi:10.1093/hmg/ddn241
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The ocular albinism type 1 protein, an intracellular G protein-coupled receptor, regulates melanosome transport in pigment cells
1 San Raffaele Scientific Institute, DIBIT, Via Olgettina 58, 20132 Milan, Italy 2 Department of Experimental Medicine, University of Genoa Medical School, Via de Toni 14, 16132 Genoa, Italy 3 Division of Basic Medical Sciences, St George's, University of London, London SW17 0RE, UK 4 TIGEM, Telethon Institute of Genetics and Medicine, Via Pietro Castellino 111, 80131 Napoli, Italy 5 Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, 41100 Modena, Italy
* To whom correspondence should be addressed. Tel: +39 02 2643 4729; Fax: +39 02 2643 4723; Email: schiaffino.mariavittoria{at}hsr.it
Received July 19, 2008; Accepted August 11, 2008
The protein product of the ocular albinism type 1 gene, named OA1, is a pigment cell-specific G protein-coupled receptor exclusively localized to intracellular organelles, namely lysosomes and melanosomes. Loss of OA1 function leads to the formation of macromelanosomes, suggesting that this receptor is implicated in organelle biogenesis, however the mechanism involved in the pathogenesis of the disease remains obscure. We report here the identification of an unexpected abnormality in melanosome distribution both in retinal pigment epithelium (RPE) and skin melanocytes of Oa1-knock-out (KO) mice, consisting in a displacement of the organelles from the central cytoplasm towards the cell periphery. Despite their depletion from the microtubule (MT)-enriched perinuclear region, Oa1-KO melanosomes were able to aggregate at the centrosome upon disruption of the actin cytoskeleton or expression of a dominant-negative construct of myosin Va. Consistently, quantification of organelle transport in living cells revealed that Oa1-KO melanosomes displayed a severe reduction in MT-based motility; however, this defect was rescued to normal following inhibition of actin-dependent capture at the cell periphery. Together, these data point to a defective regulation of organelle transport in the absence of OA1 and imply that the cytoskeleton might represent a downstream effector of this receptor. Furthermore, our results enlighten a novel function for OA1 in pigment cells and suggest that ocular albinism type 1 might result from a different pathogenetic mechanism than previously thought, based on an organelle-autonomous signalling pathway implicated in the regulation of both membrane traffic and transport.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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