@article{HankeGogokhiaZhangFredericketal.2016, author = {Hanke-Gogokhia, Christin and Zhang, Houbin and Frederick, Jeanne M. and Baehr, Wolfgang}, title = {The Function of Arf-like Proteins ARL2 and ARL3 in Photoreceptors}, series = {Retinal Degenerative Diseases : Mechanisms and Experimental Therapy}, volume = {854}, journal = {Retinal Degenerative Diseases : Mechanisms and Experimental Therapy}, editor = {Rickman, CB and LaVail, MM and Anderson, RE and Grimm, C and Hollyfield, J and Ash, J}, publisher = {Springer International Publishing AG}, address = {Cham}, isbn = {978-3-319-17121-0; 978-3-319-17120-3}, issn = {0065-2598}, doi = {10.1007/978-3-319-17121-0_87}, pages = {655 -- 661}, year = {2016}, abstract = {Arf-like proteins (ARLs) are ubiquitously expressed small G proteins of the RAS superfamily. In photoreceptors, ARL2 and ARL3 participate in the trafficking of lipidated membrane-associated proteins and colocalize in the inner segment with UNC119A and PDE delta. UNC119A and PDE delta are acyl-and prenyl-binding proteins, respectively, involved in trafficking of acylated (transducin-alpha subunit, nephrocystin NPHP3) and prenylated proteins (GRK1, PDE6). Germline Arl3 knockout mice do not survive beyond postnatal day 21 and display ciliary defects in multiple organs (kidney, liver and pancreas) as well as retinal degeneration. Conditional knockouts will be necessary to delineate mechanisms of protein transport in retina disease.}, language = {en} } @article{HankeGogokhiaWuGerstneretal.2016, author = {Hanke-Gogokhia, Christin and Wu, Zhijian and Gerstner, Cecilia D. and Frederick, Jeanne M. and Zhang, Houbin and Baehr, Wolfgang}, title = {Arf-like Protein 3 (ARL3) Regulates Protein Trafficking and Ciliogenesis in Mouse Photoreceptors}, series = {The journal of biological chemistry}, volume = {291}, journal = {The journal of biological chemistry}, publisher = {American Society for Biochemistry and Molecular Biology}, address = {Bethesda}, issn = {0021-9258}, doi = {10.1074/jbc.M115.710954}, pages = {7142 -- 7155}, year = {2016}, abstract = {Arf-like protein 3 (ARL3) is a ubiquitous small GTPase expressed in ciliated cells of plants and animals. Germline deletion of Arl3 in 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)) Arl3 deletions. 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.}, language = {en} } @article{RonquilloHankeGogokhiaReveloetal.2016, author = {Ronquillo, Cecinio C. and Hanke-Gogokhia, Christin and Revelo, Monica P. and Frederick, Jeanne M. and Jiang, Li and Baehr, Wolfgang}, title = {Ciliopathy-associated IQCB1/NPHP5 protein is required for mouse photoreceptor outer segment formation}, series = {The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology}, volume = {30}, journal = {The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology}, publisher = {Federation of American Societies for Experimental Biology}, address = {Bethesda}, issn = {0892-6638}, doi = {10.1096/fj.201600511R}, pages = {3400 -- 3412}, year = {2016}, abstract = {Null mutations in the human IQCB1/NPHP5 (nephrocystin-5) gene that encodes NPHP5 are the most frequent cause of Senior-LOken syndrome, a ciliopathy that is characterized by Leber congenital amaurosis and nephronophthisis. We generated germline Nphp5-knockout mice by placing a -Geo gene trap in intron 4, thereby truncating NPHP5 at Leu87 and removing all known functional domains. At eye opening, Nphp5(-/-) mice exhibited absence of scotopic and photopic electroretinogram responses, a phenotype that resembles Leber congenital amaurosis. Outer segment transmembrane protein accumulation in Nphp5(-/-) endoplasmic reticulum was evident as early as postnatal day (P)6. EGFP-CETN2, a centrosome and transition zone marker, identified basal bodies in Nphp5(-/-) photoreceptors, but without fully developed transition zones. Ultrastructure of P6 and 10 Nphp5(-/-) photoreceptors revealed aberrant transition zones of reduced diameter. Nphp5(-/-) photoreceptor degeneration was complete at 1 mo of age but was delayed significantly in Nphp5(-/-);Nrl(-/-) (cone only) retina. Nphp5(-/-) mouse embryonic fibroblast developed normal cilia, and Nphp5(-/-) kidney histology at 1 yr of age showed no significant pathology. Results establish that nephrocystin-5 is essential for photoreceptor outer segment formation but is dispensable for kidney and mouse embryonic fibroblast ciliary formation.}, language = {en} } @phdthesis{HankeGogokhia2016, author = {Hanke-Gogokhia, Christin}, title = {Small GTPase ARL3-GTP is key molecule in transition zone formation and trafficking of ciliary cargo in mouse photoreceptors}, school = {Universit{\"a}t Potsdam}, pages = {166}, year = {2016}, language = {en} }