Decoding Cilia Function

Avidor‐Reiss, Tomer; Maer, Andreia; Koundakjian, Edmund J.; Polyanovsky, Andrey; Keil, Thomas A.; Subramaniam, Shankar; Zuker, Charles S.

doi:10.1016/s0092-8674(04)00412-x

Cited by 477 publications

(210 citation statements)

References 44 publications

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“…Both the anterograde and retrograde motors have the same effect on Hh signaling: both are required for activation of Hh targets in the neural tube and for processing of Gli3. A dedicated role of IFT proteins for cilia formation and function is supported by the existence of a ciliary proteome, which includes the IFT proteins, that is found specifically in organisms with cilia or flagella (33,34). The absence of IFT proteins in organisms that lack cilia argues that IFT proteins are required only for the production and maintenance of cilia and not for other intracellular transport processes.…”

Section: Discussionmentioning

confidence: 99%

Cilia and Hedgehog responsiveness in the mouse

Huangfu

Anderson

2005

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

746

786

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Section: Discussionmentioning

confidence: 99%

Cilia and Hedgehog responsiveness in the mouse

Huangfu

Anderson

2005

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

746

786

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“…Whereas the kinesin-2 complex has been shown to participate in compartmentalized ciliogenesis in Drosophila sensory cilia and inter-segmental transport in mouse retina (43,44), the function of the dynein-dynactin complex in the retina is poorly understood. The dynactin subunits p50-dynamitin and p150…”

Section: Discussionmentioning

confidence: 99%

RPGR-ORF15, Which Is Mutated in Retinitis Pigmentosa, Associates with SMC1, SMC3, and Microtubule Transport Proteins

Khanna

Hurd

Lillo

et al. 2005

Journal of Biological Chemistry

154

176

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Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene account for almost 20% of patients with retinitis pigmentosa. Most mutations are detected in alternatively spliced RPGR-ORF15 isoform(s), which are primarily but not exclusively expressed in the retina. We show that, in addition to the axoneme, the RPGR-ORF15 protein is localized to the basal bodies of photoreceptor connecting cilium and to the tip and axoneme of sperm flagella. Mass spectrometric analysis of proteins that were immunoprecipitated from the retinal axoneme-enriched fraction using an anti-ORF15 antibody identified two chromosome-associated proteins, structural maintenance of chromosomes (SMC) 1 and SMC3. Using pulldown assays, we demonstrate that the interaction of RPGR with SMC1 and SMC3 is mediated, at least in part, by the RCC1-like domain of RPGR. This interaction was not observed with phosphorylation-deficient mutants of SMC1. Both SMC1 and SMC3 localized to the cilia of retinal photoreceptors and Madin-Darby canine kidney cells, suggesting a broader physiological relevance of this interaction. Additional immunoprecipitation studies revealed the association of RPGR-ORF15 isoform(s) with the intraflagellar transport polypeptide IFT88 as well as microtubule motor proteins, including KIF3A, p150Glued , and p50-dynamitin. Inhibition of dynein function by overexpressing p50 abrogated the localization of RPGR-ORF15 to basal bodies. Taken together, these results provide novel evidence for the possible involvement of RPGR-ORF15 in microtubule organization and regulation of transport in primary cilia. X-linked retinitis pigmentosa (XLRP)4 (MIM 312610) is a relatively severe and genetically heterogeneous inherited retinal degeneration.RP3 is the major subtype of XLRP accounting for over 70% of affected families (1, 2). The RP3 gene, called retinitis pigmentosa GTPase regulator (RPGR), encodes several distinct alternatively spliced transcripts that are widely expressed (3-5). Mutations in the constitutive RPGR protein of 815 amino acids are detected in ϳ20% of XLRP (6). Subsequent studies revealed an unusual exon, ORF15 (immediately following exon 15) encoding a Gly-and Glu-rich carboxyl-terminal domain of 567 amino acids; mutations in ORF15 accounted for an additional 50% of XLRP patients and 25% of RP males with no family history (7-9). Several distinct RPGR isoforms that include complete or part of ORF15 (RPGR-ORF15) are detected preferentially, but not exclusively, in the retina (7, 10) and localized to the connecting cilium and/or outer segments of photoreceptors (11-13).The amino-terminal region of RPGR (termed RCC1-like domain, RLD) shows homology to RCC1, a guanine nucleotide exchange factor for Ran, a GTPase involved in nucleocytoplasmic transport (14). Hence, RPGR was predicted to be a guanine nucleotide exchange factor for a small GTP-binding protein. However, no such activity or interaction has yet been demonstrated. Yeast two-hybrid analysis using RPGR-RLD had previously identified two proteins, RPGRIP1 (RPGR-interacting prot...

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“…When Smo was expressed in Madin-Darby canine kidney cells, it was not localized to cilia unless the pathway was activated by treatment with Hh. This signal-dependant localization is reminiscent of the situation in Drosophila, where Smo activity correlates with its cell surface localization, although, except sensory neurones and spermatids, all other cells in Drosophila do not have cilia (42).…”

Section: Discussionmentioning

confidence: 75%