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Caenorhabditis elegans DYF-2, an orthologue of human WDR19, is a component of the intraflagellar transport machinery in sensory Cilia
Södertörn University, School of Life Sciences. Karolinska Institute.
Simon Fraser University, Burnaby, British Columbia, Canada.
University of California, Davis, USA.
University of Alabama at Birmingham Medical Center, Birmingham, USA.
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2006 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 17, no 11, 4801-4811 p.Article in journal (Refereed) Published
Abstract [en]

The intraflagellar transport (IFT) machinery required to build functional cilia consists of a multisubunit complex whose molecular composition, organization, and function are poorly understood. Here, we describe a novel tryptophan-aspartic acid (WD) repeat (WDR) containing IFT protein from Caenorhabditis elegans, DYF-2, that plays a critical role in maintaining the structural and functional integrity of the IFT machinery. We determined the identity of the dyf-2 gene by transgenic rescue of mutant phenotypes and by sequencing of mutant alleles. Loss of DYF-2 function selectively affects the assembly and motility of different IFT components and leads to defects in cilia structure and chemosensation in the nematode. Based on these observations, and the analysis of DYF-2 movement in a Bardet-Biedl syndrome mutant with partially disrupted IFT particles, we conclude that DYF-2 can associate with IFT particle complex B. At the same time, mutations in dyf-2 can interfere with the function of complex A components, suggesting an important role of this protein in the assembly of the IFT particle as a whole. Importantly, the mouse orthologue of DYF-2, WDR19, also localizes to cilia, pointing to an important evolutionarily conserved role for this WDR protein in cilia development and function.

Place, publisher, year, edition, pages
2006. Vol. 17, no 11, 4801-4811 p.
National Category
Cell Biology
URN: urn:nbn:se:sh:diva-14274DOI: 10.1091/mbc.E06-04-0260ISI: 000241993500019PubMedID: 16957054ScopusID: 2-s2.0-33750514794OAI: diva2:468780
Available from: 2011-12-21 Created: 2011-12-20 Last updated: 2016-11-28Bibliographically approved
In thesis
1. The study of sensory cilia development in caenorhabditis elegans
Open this publication in new window or tab >>The study of sensory cilia development in caenorhabditis elegans
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cilia and flagella are widespread eukaryotic subcellular components that are conserved from green algae to mammals. In different organisms they function in cell motility, movement of extracellular fluids and sensory reception. While the function and structural description of cilia and flagella are well established, very little is known about the developmental mechanisms by which cilia are generated and shaped and how their components are assembled into functional machineries. To answer these questions, we used sensory cilia development in the nematode Caenorhabditis elegansas a model system.

The work described here developed from the initial discovery of the ciliogenic properties of the gene daf-19, which encodes the sole C. elegans member of the RFX-type transcription factors. All members of the RFX transcription factor family are characterized by the presence of a conserved DNA binding domain, which recognizes special motifs (X-boxes) in promoters of its target genes. By using a genome search approach for X-box promoter motif-containing genes (xbx genes) we identified a list of about 750 xbx genes (candidates). This list comprises some already known ciliary genes as well as new genes, many of which we hypothesize to be important for cilia development and functioning.

A computational search for X-box motifs in the C. briggsae genome has demonstrated strong conservation of this motif between closely related nematode species. To find out whether RFX-type transcription factors can also regulate ciliogenic pathways in other organisms, we applied a similar search strategy to distant species such as the fruit fly Drosophila. Using X-box consensus sequences with varying degrees of refinement and subsequent gene expression analysis, we were able to identify a set of Drosophila xbx genes. Intriguingly, the majority of fly xbx genes that have homologs in C. elegans were down regulated in dRfx fly mutants, suggesting an evolutionary conserved role for RFX-type transcription factors in the regulation of ciliary genes.

Using X-box matches as a prediction tool we were able to identify novel ciliary genes, dyf-2 and dyf-11, in the C. elegans genome. We cloned these genes by transgenic rescue of mutant phenotypes and by sequencing of mutant alleles. Loss of DYF-2 and DYF-11 functions selectively affects the assembly and motility of different intraflagellar transport (IFT) components, resulting in compromised protein transport within cilia, and subsequently in defective cilia structures and sensory functions. Importantly, the mouse orthologs of DYF-2 and DYF-11 also localize to cilia, pointing to evolutionarily conserved roles for these proteins in cilia biogenesis.

In conclusion, our studies of the regulation of sensory cilia formation demonstrated how contributions of multiple factors are integrated into a developmental module that leads to the formation of the primary sensory organs, cilia. In addition, data obtained during the course of this study provide a useful resource for researchers interested in further identification and study of new genes implicated in cilia biogenesis and will have a significant impact on the understanding and treatment of cilia-based pathologies in humans.

Place, publisher, year, edition, pages
Stockholm: Karolinska Institutet, 2008. 44 p.
National Category
Biological Sciences
urn:nbn:se:sh:diva-31234 (URN)978-91-7140-992-8 (ISBN)
Public defence
2008-01-25, MA648, Alfred Nobels allé 7, Huddinge, 09:00 (English)
Available from: 2016-11-28 Created: 2016-11-28 Last updated: 2016-11-28Bibliographically approved

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