Ciliogenesis: building the cell's antenna

Department of Biochemistry and Biophysics, University of California, San Francisco, BOX 2200 GH-N372F, 600 16th Street, San Francisco, California 94158, USA.
Nature Reviews Molecular Cell Biology (Impact Factor: 36.46). 04/2011; 12(4):222-34. DOI: 10.1038/nrm3085
Source: PubMed

ABSTRACT The cilium is a complex organelle, the assembly of which requires the coordination of motor-driven intraflagellar transport (IFT), membrane trafficking and selective import of cilium-specific proteins through a barrier at the ciliary transition zone. Recent findings provide insights into how cilia assemble and disassemble in synchrony with the cell cycle and how the balance of ciliary assembly and disassembly determines the steady-state ciliary length, with the inherent length-dependence of IFT rendering the ciliary assembly rate a decreasing function of length. As cilia are important in sensing and processing developmental signals and directing the flow of fluids such as mucus, defects in ciliogenesis and length control are likely to underlie a range of cilium-related human diseases.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Over the past two decades or so, our understanding of gene function has come primarily from animal model organisms. In cases, when human disease alleles were found in developmental key genes, the translational aspect was deduced from the experimental animal model data. With the rapid improvement of sequencing technologies and data processing, we envisage that rare genetic disease alleles will be identified quickly and easily. As a consequence, experiments in animal models will be necessary to elucidate disease mechanisms, resulting in a workflow from the disease allele to experimentation in animal models. The Xenopus embryo is particularly qualified for this scenario. Knockdown of single or multiple gene functions, easy epistatic experimental setups as well as phenotypic readouts within a few days are only some of the advantages that the frog has to offer. In this review, we describe how the experimental advantages of the frog Xenopus have helped to unravel the function of a specific class of disease genes resulting in ciliopathies.
    06/2015; 3(2). DOI:10.1007/s40139-015-0074-2
  • [Show abstract] [Hide abstract]
    ABSTRACT: TTLL3 and TTLL8 are tubulin glycine ligases catalyzing posttranslational glycylation of microtubules. We show here for the first time that these enzymes are required for robust formation of primary cilia. We further discover the existence of primary cilia in colon and demonstrate that TTLL3 is the only glycylase in this organ. As a consequence, colon epithelium shows a reduced number of primary cilia accompanied by an increased rate of cell division in TTLL3-knockout mice. Strikingly, higher proliferation is compensated by faster tissue turnover in normal colon. In a mouse model for tumorigenesis, lack of TTLL3 strongly promotes tumor development. We further demonstrate that decreased levels of TTLL3 expression are linked to the development of human colorectal carcinomas. Thus, we have uncovered a novel role for tubulin glycylation in primary cilia maintenance, which controls cell proliferation of colon epithelial cells and plays an essential role in colon cancer development.
    The EMBO Journal 08/2014; DOI:10.15252/embj.201488466 · 10.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The primary cilium, which disassembles before mitotic entry and reassembles after mitosis, organizes many signal transduction pathways that are crucial for cell life and individual development. However, how ciliogenesis is regulated during the cell cycle remains largely unknown. Here we show that GSK3β, Dzip1, and Rab8 co-regulate ciliogenesis by promoting the assembly of the ciliary membrane after mitosis. Immunofluorescence and super-resolution microscopy showed that Dzip1 was localized to the periciliary diffusion barrier and enriched at the mother centriole. Knockdown of Dzip1 by short hairpin RNAs led to failed ciliary localization of Rab8, and Rab8 accumulation at the basal body. Dzip1 preferentially bound to Rab8GDP and promoted its dissociation from its inhibitor GDI2 at the pericentriolar region, as demonstrated by sucrose gradient centrifugation of purified basal bodies, immunoprecipitation, and acceptor-bleaching fluorescence resonance energy transfer assays. By means of in vitro phosphorylation, in vivo gel shift, phospho-peptide identification by mass spectrometry, and GST pulldown assays, we demonstrated that Dzip1 was phosphorylated by GSK3β at S520 in G0 phase, which increased its binding to GDI2 to promote the release of Rab8GDP at the cilium base. Moreover, ciliogenesis was inhibited by overexpression of the GSK3β-nonphosphorylatable Dzip1 mutant or by disabling of GSK3β by specific inhibitors or knockout of GSK3β in cells. Collectively, our data reveal a unique cascade consisting of GSK3β, Dzip1, and Rab8 that regulates ciliogenesis after mitosis.
    PLoS Biology 04/2015; 13(4):e1002129. DOI:10.1371/journal.pbio.1002129 · 11.77 Impact Factor

Wallace Marshall