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Identification of novel regulatory factor X (RFX) target genes by comparative genomics in Drosophila species
Université de Lyon, France.
Université de Lyon, France / University of Massachusetts Medical School, USA.
Södertörn University, School of Life Sciences. Karolinska Institute.
Université de Lyon, France.
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2007 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 8, no 9, R195- p.Article in journal (Refereed) Published
Abstract [en]

Background: Regulatory factor X (RFX) transcription factors play a key role in ciliary assembly in nematode, Drosophila and mouse. Using the tremendous advantages of comparative genomics in closely related species, we identified novel genes regulated by dRFX in Drosophila. Results: We first demonstrate that a subset of known ciliary genes in Caenorhabditis elegans and Drosophila are regulated by dRFX and have a conserved RFX binding site (X-box) in their promoters in two highly divergent Drosophila species. We then designed an X-box consensus sequence and carried out a genome wide computer screen to identify novel genes under RFX control. We found 412 genes that share a conserved X-box upstream of the ATG in both species, with 83 genes presenting a more restricted consensus. We analyzed 25 of these 83 genes, 16 of which are indeed RFX target genes. Two of them have never been described as involved in ciliogenesis. In addition, reporter construct expression analysis revealed that three of the identified genes encode proteins specifically localized in ciliated endings of Drosophila sensory neurons. Conclusion: Our X-box search strategy led to the identification of novel RFX target genes in Drosophila that are involved in sensory ciliogenesis. We also established a highly valuable Drosophila cilia and basal body dataset. These results demonstrate the accuracy of the X-box screen and will be useful for the identification of candidate genes for human ciliopathies, as several human homologs of RFX target genes are known to be involved in diseases, such as Bardet-BiedI syndrome.

Place, publisher, year, edition, pages
2007. Vol. 8, no 9, R195- p.
National Category
Microbiology Genetics
Identifiers
URN: urn:nbn:se:sh:diva-14245DOI: 10.1186/gb-2007-8-9-r195ISI: 000252100800021PubMedID: 17875208Scopus ID: 2-s2.0-44049101446OAI: oai:DiVA.org:sh-14245DiVA: diva2:467324
Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-07-18Bibliographically 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
Identifiers
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)
Opponent
Supervisors
Available from: 2016-11-28 Created: 2016-11-28 Last updated: 2016-11-28Bibliographically approved

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