Genetic Evidence for Selective Transport of Opsin and Arrestin by Kinesin-II in Mammalian Photoreceptors

Marszalek, Joseph R.; Liu, Xinran; Roberts, Elizabeth A.; Chui, Daniel; Marth, Jamey D.; Williams, David S.; Goldstein, Lawrence S.B.

doi:10.1016/s0092-8674(00)00023-4

Cited by 367 publications

(339 citation statements)

References 48 publications

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“…Interestingly, arrestin immunoreactivity accumulates at these structures in Xenopus retinas during dark adaptation, suggesting that arrestin is a cargo for microtubule-based transport after changes in lighting conditions (McGinnis et al, 2002). Consistent with the role of microtubular tracks in arrestin transport, arrestin was observed to accumulate at the inner segments of rods after conditional inactivation of the KIF3A subunit of kinesin II (Marszalek et al, 2000). However, future studies will be needed to investigate the nature of the interaction of arrestin with motor proteins or other components of the polarized transport machinery.…”

Section: Discussionmentioning

confidence: 56%

Light-Dependent Translocation of Arrestin in the Absence of Rhodopsin Phosphorylation and Transducin Signaling

2003

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Visual arrestin plays a crucial role in the termination of the light response in vertebrate photoreceptors by binding selectively to lightactivated, phosphorylated rhodopsin. Arrestin localizes predominantly to the inner segments and perinuclear region of dark-adapted rod photoreceptors, whereas light induces redistribution of arrestin to the rod outer segments. The mechanism by which arrestin redistributes in response to light is not known, but it is thought to be associated with the ability of arrestin to bind photolyzed, phosphorylated rhodopsin in the outer segment. In this study, we show that light-driven translocation of arrestin is unaffected in two different mouse models in which rhodopsin phosphorylation is lacking. We further show that arrestin movement is initiated by rhodopsin but does not require transducin signaling. These results exclude passive diffusion and point toward active transport as the mechanism for lightdependent arrestin movement in rod photoreceptor cells.

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Section: Discussionmentioning

confidence: 56%

Light-Dependent Translocation of Arrestin in the Absence of Rhodopsin Phosphorylation and Transducin Signaling

2003

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“…The connecting cilium between the inner and outer segment of the retina is thought to be the exclusive route of transport of newly synthesized proteins from the inner to outer segment. Disruption of this process in a conditional kinesin-II knockout mouse model has been shown to cause retinal degeneration, demonstrating that IFT is required for maintaining the outer segment of photoreceptor cells (14). We show that the loss of Bbs4 does not prevent initial formation of photoreceptor outer segments, and we propose that its absence compromises the intracellular transport that is required for maintaining the rapidly regenerating outer segments of these cells.…”

Section: Discussionmentioning

confidence: 71%

Bardet–Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly

Mykytyn

Mullins²,

Andrews³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

310

303

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The functions of the proteins encoded by the Bardet-Biedl syndrome (BBS) genes are unknown. Mutations in these genes lead to the pleiotropic human disorder BBS, which is characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Secondary features include diabetes mellitus and hypertension. Recently, it has been suggested that the BBS phenotypes are the result of a lack of cilia formation or function. In this study, we show that mice lacking the Bbs4 protein have major components of the human phenotype, including obesity and retinal degeneration. We show that Bbs4-null mice develop both motile and primary cilia, demonstrating that Bbs4 is not required for global cilia formation. Interestingly, male Bbs4-null mice do not form spermatozoa flagella, and BBS4 retinopathy involves apoptotic death of photoreceptors, the primary ciliated cells of the retina. These mutation data demonstrate a connection between the function of a BBS protein and cilia. To further evaluate an association between cilia and BBS, we performed homology comparisons of BBS proteins in model organisms and find that BBS proteins are specifically conserved in ciliated organisms.B ardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder with linkage to eight loci. Six BBS genes (BBS1, BBS2, BBS4, BBS6, BBS7, and BBS8) have been identified (1-7). With the exception of BBS6, which has similarity to type II chaperonins (8), BBS proteins do not show extensive homology with proteins of known function. BBS4 and BBS8 contain tetratricopeptide repeat domains, and a region of BBS8 shows similarity to the prokaryotic pilF domain. Based on the observations that BBS8 localizes to the basal body of ciliated cells and expression of the Caenorhabditis elegans orthologues of several BBS proteins are limited to ciliated cells, it has been hypothesized that BBS is the result of a defect in cilia assembly or function (7). We previously used positional cloning to identify the human BBS4 gene (3). To help elucidate the function of the BBS proteins, we have now targeted the Bbs4 gene in mice. Bbs4 Ϫ/Ϫ mice recapitulate aspects of the human phenotype: they become obese, fail to reproduce, and display retinal degeneration. We show the presence of both motile and primary cilia in these mice, demonstrating that Bbs4 deficiency does not prevent global ciliogenesis. Interestingly, male knockout mice have a complete lack of flagella, demonstrating that the Bbs4 protein is necessary for flagella formation during spermatogenesis. Furthermore, Bbs4-null mice undergo retinal degeneration due principally to photoreceptor cell loss associated with outer segment attenuation, suggesting a role for BBS proteins in maintenance of sensory cilia. These data demonstrate a role for BBS proteins in facets of cilia function. Materials and MethodsConstruction of the Bbs4 Gene Targeting Vector. BLAST analysis of the Celera mouse fragment database with the human BBS4 cDNA sequence identified sequences corresponding to...

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“…cre Ksp transgenic mice (15) that express Cre recombinase exclusively in tubular epithelial cells in the kidney and developing genitourinary tract were crossed with Kif3a fl/ϩ mice (22) containing two loxP sites flanking exon 2 of the Kif3a gene (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease

Lin

Hiesberger

Cordes

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

537

475

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Genetic Evidence for Selective Transport of Opsin and Arrestin by Kinesin-II in Mammalian Photoreceptors

Cited by 367 publications

References 48 publications

Light-Dependent Translocation of Arrestin in the Absence of Rhodopsin Phosphorylation and Transducin Signaling

Light-Dependent Translocation of Arrestin in the Absence of Rhodopsin Phosphorylation and Transducin Signaling

Bardet–Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly

Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease

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