Intraflagellar transport and cilia-dependent diseases

doi:10.1016/S0962-8924(02)02410-8

Trends in Cell Biology

Volume 12, Issue 12, 1 December 2002, Pages 551-555

https://doi.org/10.1016/S0962-8924(02)02410-8 Get rights and content

Abstract

Intraflagellar transport involves the movement of large protein particles along ciliary microtubules and is required for the assembly and maintenance of eukaryotic cilia and flagella. Intraflagellar-transport defects in the mouse cause a range of diseases including polycystic kidney disease, retinal degeneration and the laterality abnormality situs inversus, highlighting the important role that motile, sensory and primary cilia play in vertebrates.

Section snippets

Intraflagellar transport

IFT is an intracellular motility system, by which large protein complexes, called IFT particles, are transported bidirectionally between the flagellar membrane and the outer doublet microtubules of cilia and flagella (Fig. 1b). The IFT particles are not components of the axoneme or membrane but are hypothesized to transport axonemal and membrane proteins. IFT was first described in Chlamydomonas [6] and has subsequently been found to be essential for the assembly of motile and sensory cilia in

Polycystic kidney disease

Kidney epithelial cells have non-motile primary cilia projecting from their apical surface into the lumen of the ducts and tubules of the nephrons [19] (Fig. 2). Insight into the importance of these cilia came from recent studies of the Tg737 gene. Mice homozygous for a Tg737 mutation develop PKD and hepatic fibrosis similar to what is observed in humans with autosomal recessive PKD [20]. The Tg737 gene encodes a protein homologous to the IFT88 subunit of the Chlamydomonas IFT particle [13],

Retinal degeneration

The outer segments of vertebrate photoreceptor rods and cones are formed from primary cilia. During development of the outer segment, large amounts of lipid and protein are transported into the distal segment of the cilium and assembled into the membranous disks. In the mature photoreceptor, the distal portion of the outer segment is so highly modified that it no longer resembles a cilium (Fig. 3). However, a short segment of the cilium, called the connecting cilium, remains to connect the

Laterality defects

During mammalian embryonic development, the bilateral symmetry of the early embryo is broken to give rise to the left–right asymmetry that is seen in adult animals. Failure in this process can lead to a complete reversal of the internal viscera, which is a benign condition called situs inversus. Partial reversals are much more harmful and can cause internal-organ defects, congenital heart disease and prenatal lethality [32]. Embryonic cilia were seen to be likely to play a role in breaking

Concluding remarks

The initial observations of IFT in Chlamydomonas have enabled the discovery that all eukaryotic nonmotile and motile cilia require IFT, and that the lack of cilia might lead to human pathologies. These pathologies include PKD, retinal degeneration and situs inversus, but additional cilia-dependent pathologies clearly remain to be discovered. There are already indications of this, because the Tg737 mouse also develops liver cysts [20], hydrocephaly [43] and polydactyly [20], and is male sterile

Acknowledgements

Our work is supported by National Institutes of Health grants GM-60992 to G.J.P. and GM-14642 to J.L.R.

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Translocation of channelrhodopsins (ChRs) is mediated by the intraflagellar transport (IFT) machinery. However, the functional role of the network involving photoreceptors, IFT and other proteins in controlling algal ciliary motility is still not fully delineated. In the current study, we have identified two important motifs at the C-terminus of ChR1, VXPX and LKNE. VXPX is a known ciliary targeting sequence in animals, and LKNE is a well-known SUMOylation motif. To the best of our knowledge, this study gives prima facie insight into the role of SUMOylation in Chlamydomonas. We prove that VMPS of ChR1 is important for interaction with GTPase CrARL11. We show that SUMO motifs are present in the C-terminus of putative ChR1s from green algae. Performing experiments with n-Ethylmaleimide (NEM) and Ubiquitin-like protease 1 (ULP-1), we show that SUMOylation may modulate ChR1 protein in Chlamydomonas. Experiments with 2D08, a known sumoylation blocker, increased the concentration of ChR1 protein. Finally, we show the endogenous SUMOylated proteins (SUMOylome) of C. reinhardtii, identified by using immunoprecipitation followed by nano-LC-MS/MS detection. This report establishes a link between evolutionarily conserved SUMOylation and ciliary machinery for the maintenance and functioning of cilia across the eukaryotes. Our enriched SUMOylome of C. reinhardtii comprehends the proteins related to ciliary development and photo-signaling, along with the orthologue(s) associated to human ciliopathies as SUMO targets.
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The primary cilium is a highly specialized and evolutionary conserved organelle in eukaryotes that plays a significant role in cell signaling and trafficking. Over the past few decades tremendous progress has been made in understanding the physiology of cilia and the underlying pathomechanisms of various ciliopathies. Syndromic ciliopathies consist of a group of disorders caused by ciliary dysfunction or abnormal ciliogenesis. These disorders have multiorgan involvement in addition to retinal degeneration underscoring the ubiquitous distribution of primary cilia in different cell types. Genotype-phenotype correlation is often challenging due to the allelic heterogeneity and pleiotropy of these disorders. In this review, we discuss the clinical and genetic features of syndromic ciliopathies with a focus on Bardet-Biedl syndrome (BBS) as a representative disorder. We discuss the structure and function of primary cilia and their role in retinal photoreceptors. We describe the progress made thus far in understanding the functional and genetic characterization including expression quantitative trait locus (eQTL) analysis of BBS genes. In the future directions section, we discuss the emerging technologies, such as gene therapy, as well as anticipated challenges and their implications in therapeutic development for ciliopathies.
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Any proposed mechanism for organelle size control should be able to account not only for average size but also for the variation in size. We analyzed cell-to-cell variation and within-cell variation of length for the two flagella in Chlamydomonas, finding that cell-to-cell variation is dominated by cell size, whereas within-cell variation results from dynamic fluctuations. Fluctuation analysis suggests tubulin assembly is not directly coupled with intraflagellar transport (IFT) and that the observed length fluctuations reflect tubulin assembly and disassembly events involving large numbers of tubulin dimers. Length variation is increased in long-flagella mutants, an effect consistent with theoretical models for flagellar length regulation. Cells with unequal flagellar lengths show impaired swimming but improved gliding, raising the possibility that cells have evolved mechanisms to tune biological noise in flagellar length. Analysis of noise at the level of organelle size provides a way to probe the mechanisms determining cell geometry.
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Pkd2 Deficiency in Embryonic Aqp2<sup>+</sup> Progenitor Cells Is Sufficient to Cause Severe Polycystic Kidney Disease
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Trends in Cell Biology

ReviewIntraflagellar transport and cilia-dependent diseases

Abstract

Section snippets

Intraflagellar transport

Polycystic kidney disease

Retinal degeneration

Laterality defects

Concluding remarks

Acknowledgements

Cell Biol. Int.

J. Ultrastruct. Res.

Trends Cell Biol.

Brain Res. Mol. Brain Res.

J. Biol. Chem.

Curr. Biol.

Curr. Biol.

Cell

Cell

Mol. Cell

Neuroscience

Introduction to cilia and flagella

Intraflagellar transport: the eyes have it

J. Cell Biol.

A motility in the eukaryotic flagellum unrelated to flagellar beating

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

The Chlamydomonas kinesin-like protein FLA10 is involved in motility associated with the flagellar membrane

J. Cell Biol.

Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons

J. Cell Biol.

The DHC1b (DHC2) isoform of cytoplasmic dynein is required for flagellar assembly

J. Cell Biol.

Cytoplasmic dynein heavy chain 1b is required for flagellar assembly in Chlamydomonas

Mol. Biol. Cell

Transport of a novel complex in the cytoplasmic matrix of Chlamydomonas flagella

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

Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene Tg737, are required for assembly of cilia and flagella

J. Cell Biol.

Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi

Nat. Cell Biol.

Review
Intraflagellar transport and cilia-dependent diseases