title: Arf-like Protein 3 (ARL3) Regulates Protein Trafficking and Ciliogenesis in Mouse Photoreceptors.
abstract: Arf-like protein 3 (ARL3) is a ubiquitous small GTPase expressed in ciliated cells of plants and animals. Germline deletion ofArl3in mice causes multiorgan ciliopathy reminiscent of Bardet-Biedl or Joubert syndromes. As photoreceptors are elegantly compartmentalized and have cilia, we probed the function of ARL3 (ADP-ribosylation factor (Arf)-like 3 protein) by generating rod photoreceptor-specific (prefix(rod)) and retina-specific (prefix(ret))Arl3deletions. In predegenerate(rod)Arl3(-/-)mice, lipidated phototransduction proteins showed trafficking deficiencies, consistent with the role of ARL3 as a cargo displacement factor for lipid-binding proteins. By contrast,(ret)Arl3(-/-)rods and cones expressing Cre recombinase during embryonic development formed neither connecting cilia nor outer segments and degenerated rapidly. Absence of cilia infers participation of ARL3 in ciliogenesis and axoneme formation. Ciliogenesis was rescued, and degeneration was reversed in part by subretinal injection of adeno-associated virus particles expressing ARL3-EGFP. The conditional knock-out phenotypes permitted identification of two ARL3 functions, both in the GTP-bound form as follows: one as a regulator of intraflagellar transport participating in photoreceptor ciliogenesis and the other as a cargo displacement factor transporting lipidated protein to the outer segment. Surprisingly, a farnesylated inositol polyphosphate phosphatase only trafficked from the endoplasmic reticulum to the Golgi, thereby excluding it from a role in photoreceptor cilia physiology.
authors.affiliation: From the Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and the Department of Biochemistry and Biology, University of Potsdam, 14476 Potsdam-Golm, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Hanke-Gogokhia
authors.affiliation: the NEI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Wu
authors.affiliation: From the Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and.
authors.forename: Cecilia D
authors.initials: CD
authors.lastname: Gerstner
authors.affiliation: From the Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and.
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Frederick
authors.affiliation: the Sichuan Provincial Key Laboratory for Human Disease Gene Study, Institute of Laboratory Medicine, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, 610072 Sichuan, China, the School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072 Sichuan, China, and houbin.zhang@gmail.com.
authors.forename: Houbin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah 84132, From the Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, and the Department of Biology, University of Utah, Salt Lake City, Utah 84112 wbaehr@hsc.utah.edu.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
mesh_terms: D020727:ADP-Ribosylation Factors / Q000172:deficiency / Q000235:genetics*; D000367:Age Factors; D000818:Animals; D002923:Cilia / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004596:Electroretinography; D004622:Embryo, Mammalian; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D055537:Light Signal Transduction; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D005136:Eye Proteins; D011993:Recombinant Fusion Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C045073:Cre recombinase; D019426:Integrases; D010744:Phosphoric Monoester Hydrolases; C490248:Arl3 protein, mouse; D020727:ADP-Ribosylation Factors
keywords: animal model; gene knock-out; lipid-binding protein; photoreceptor; protein trafficking (Golgi); retinal degeneration
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