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  • 1. Blacque, O E
    et al.
    Perens, E A
    Boroevich, K A
    Inglis, P N
    Li, C M
    Warner, A
    Khattra, J
    Holt, R A
    Ou, G S
    Mah, A K
    McKay, S J
    Huang, P
    Swoboda, Peter
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Jones, S J M
    Marra, M A
    Baillie, D L
    Moerman, D G
    Shaham, S
    Leroux, M R
    Functional genomics of the cilium, a sensory organelle2005In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 15, no 10, p. 935-941Article in journal (Refereed)
    Abstract [en]

    Cilia and flagella play important roles in many physiological processes, including cell and fluid movement, sensory perception, and development [1]. The biogenesis and maintenance of cilia depend on intraflagellar transport (IFT), a motility process that operates bidirectionally along the ciliary axoneme [1, 2]. Disruption in IFT and cilia function causes several human disorders, including polycystic kidneys, retinal dystrophy, neurosensory impairment, and Bardet-Bledl syndrome (BBS) [3-5]. To uncover new ciliary components, including IFT proteins, we compared C. elegans ciliated neuronal and nonciliated cells through serial analysis of gene expression (SAGE) and screened for genes potentially regulated by the cillogenic transcription factor, DAF-19 [6]. Using these complementary approaches, we identified numerous candidate ciliary genes and confirmed the ciliated-cell-specific expression of 14 novel genes. One of these, C27H5.7a, encodes a ciliary protein that undergoes IFT. As with other IFT proteins, its ciliary localization and transport is disrupted by mutations in IFT and bbs genes. Furthermore, we demonstrate that the ciliary structural defect of C. elegans dyf-13(mn396) mutants is caused by a mutation in C27H5.7a. Together, our findings help define a ciliary transcriptome and suggest that DYF-13, an evolutionarily conserved protein, is a novel core IFT component required for cilia function.

  • 2. Ceron, Julian
    et al.
    Swoboda, Peter
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Caenorhabditis elegans comes of age2008In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 9, no 6, p. 312-Article in journal (Other academic)
  • 3. Chen, Nansheng
    et al.
    Mah, Allan
    Blacque, Oliver E.
    Chu, Jeffrey
    Phgora, Kiran
    Bakhoum, Mathieu W.
    Newbury, C. Rebecca Hunt
    Khattra, Jaswinder
    Chan, Susanna
    Go, Anne
    Efimenko, Evgeni
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Johnsen, Robert
    Phirke, Prasad
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Swoboda, Peter
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Marra, Marco
    Moerman, Donald G.
    Leroux, Michel R.
    Baillie, David L.
    Stein, Lincoln D.
    Identification of ciliary and ciliopathy genes in Caenorhabditis elegans through comparative genomics2006In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 7, no 12, p. R126-Article in journal (Refereed)
    Abstract [en]

    Background: The recent availability of genome sequences of multiple related Caenorhabditis species has made it possible to identify, using comparative genomics, similarly transcribed genes in Caenorhabditis elegans and its sister species. Taking this approach, we have identified numerous novel ciliary genes in C. elegans, some of which may be orthologs of unidentified human ciliopathy genes. Results: By screening for genes possessing canonical X-box sequences in promoters of three Caenorhabditis species, namely C. elegans, C. briggsae and C. remanei, we identified 93 genes ( including known X-box regulated genes) that encode putative components of ciliated neurons in C. elegans and are subject to the same regulatory control. For many of these genes, restricted anatomical expression in ciliated cells was confirmed, and control of transcription by the ciliogenic DAF-19 RFX transcription factor was demonstrated by comparative transcriptional profiling of different tissue types and of daf-19(+) and daf-19(-) animals. Finally, we demonstrate that the dye-filling defect of dyf-5( mn400) animals, which is indicative of compromised exposure of cilia to the environment, is caused by a nonsense mutation in the serine/threonine protein kinase gene M04C9.5. Conclusion: Our comparative genomics-based predictions may be useful for identifying genes involved in human ciliopathies, including Bardet-Biedl Syndrome ( BBS), since the C. elegans orthologs of known human BBS genes contain X-box motifs and are required for normal dye filling in C. elegans ciliated neurons.

  • 4. Dubruille, R
    et al.
    Laurencon, A
    Vandaele, C
    Shishido, E
    Coulon-Bublex, M
    Swoboda, Peter
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Couble, P
    Kernan, M
    Durand, B
    Drosophila regulatory factor X is necessary for ciliated sensory neuron differentiation2002In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 129, no 23, p. 5487-5498Article in journal (Refereed)
    Abstract [en]

    Ciliated neurons play an important role in sensory perception in many animals. Modified cilia at dendrite endings serve as sites of sensory signal capture and transduction. We describe Drosophila mutations that affect the transcription factor RFX and genetic rescue experiments that demonstrate its central role in sensory cilium differentiation. Rfx mutant flies show defects in chemosensory and mechanosensory behaviors but have normal phototaxis, consistent with Rfx expression in ciliated sensory neurons and neuronal precursors but not in photoreceptors. The mutant behavioral phenotypes are correlated with abnormal function and structure of neuronal cilia, as shown by the loss of sensory transduction and by defects in ciliary morphology and ultrastructure. These results identify Rfx as an essential regulator of ciliated sensory neuron differentiation in Drosophild.

  • 5.
    Efimenko, Evgeni
    et al.
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Blacque, Oliver E.
    Simon Fraser University, Burnaby, British Columbia, Canada.
    Ou, Guangshuo
    University of California, Davis, USA.
    Haycraft, Courtney J.
    University of Alabama at Birmingham Medical Center, Birmingham, USA.
    Yoder, Bradley K.
    University of Alabama at Birmingham Medical Center, Birmingham, USA.
    Scholey, Jonathan M.
    University of California, Davis, USA.
    Leroux, Michel R.
    Simon Fraser University, Burnaby, British Columbia, Canada.
    Swoboda, Peter
    Södertörn University, School of Life Sciences. Karolinska Instiute.
    Caenorhabditis elegans DYF-2, an orthologue of human WDR19, is a component of the intraflagellar transport machinery in sensory Cilia2006In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 17, no 11, p. 4801-4811Article in journal (Refereed)
    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.

  • 6.
    Efimenko, Evgeni
    et al.
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Bubb, K
    Mak, H Y
    Holzman, T
    Leroux, M R
    Ruvkun, G
    Thomas, J H
    Swoboda, Peter
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Analysis of xbx genes in C-elegans2005In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 132, no 8, p. 1923-1934Article in journal (Refereed)
    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, there are many questions that remain unanswered. In particular, 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 find genes involved in cilia development we used as a search tool a promoter motif, the X-box, which participates in the regulation of certain ciliary genes in the nematode Caenorhabditis elegans. 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 cilium structure and function. We derived a C elegans X-box consensus sequence by in vivo expression analysis. We found that xbx gene expression patterns were dependent on particular X-box nucleotide compositions and the distance from the respective gene start. We propose a model where DAF-19, the RFX-type transcription factor binding to the X-box, is responsible for the development of a ciliary module in C elegans, which includes genes for cilium structure, transport machinery, receptors and other factors.

  • 7.
    Kärblane, Kairi
    et al.
    Tallinn University of Technology, Tallinn, Estonia / Competence Centre for Cancer Research, Tallinn, Estonia .
    Gerassimenko, Jelena
    Tallinn University of Technology, Tallinn, Estonia / Competence Centre for Cancer Research, Tallinn, Estonia .
    Nigul, Lenne
    Tallinn University of Technology, Tallinn, Estonia.
    Piirsoo, Alla
    Tallinn University of Technology, Tallinn, Estonia.
    Smialowska, Agata
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies. Karolinska Institutet.
    Vinkel, Kadri
    Tallinn University of Technology, Tallinn, Estonia .
    Kylsten, Per
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies.
    Ekwall, Karl
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies. Karolinska Institutet.
    Swoboda, Peter
    Karolinska Institutet.
    Truve, Erkki
    Tallinn University of Technology, Tallinn, Estonia / Competence Centre for Cancer Research, Tallinn, Estonia .
    Sarmiento, Cecilia
    Tallinn University of Technology, Tallinn, Estonia / Competence Centre for Cancer Research, Tallinn, Estonia .
    ABCE1 Is a Highly Conserved RNA Silencing Suppressor2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 2, article id e0116702Article in journal (Refereed)
    Abstract [en]

    ATP-binding cassette sub-family E member 1 (ABCE1) is a highly conserved protein among eukaryotes and archaea. Recent studies have identified ABCE1 as a ribosome-recycling factor important for translation termination in mammalian cells, yeast and also archaea. Here we report another conserved function of ABCE1. We have previously described AtRLI2, the homolog of ABCE1 in the plant Arabidopsis thaliana, as an endogenous suppressor of RNA silencing. In this study we show that this function is conserved: human ABCE1 is able to suppress RNA silencing in Nicotiana benthamiana plants, in mammalian HEK293 cells and in the worm Caenorhabditis elegans. Using co-immunoprecipitation and mass spectrometry, we found a number of potential ABCE1-interacting proteins that might support its function as an endogenous suppressor of RNA interference. The interactor candidates are associated with epigenetic regulation, transcription, RNA processing and mRNA surveillance. In addition, one of the identified proteins is translin, which together with its binding partner TRAX supports RNA interference.

  • 8.
    Laurencon, Anne
    et al.
    Université de Lyon, France.
    Dubruille, Raphaelle
    Université de Lyon, France / University of Massachusetts Medical School, USA.
    Efimenko, Evgeni
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Grenier, Guillaume
    Université de Lyon, France.
    Bissett, Ryan
    Université de Lyon, France / University of Glasgow, UK.
    Cortier, Elisabeth
    Université de Lyon, France.
    Rolland, Vivien
    Université de Lyon, France.
    Swoboda, Peter
    Södertörn University, School of Life Sciences. Karolinska Institute.
    Durand, Benedicte
    Université de Lyon, France.
    Identification of novel regulatory factor X (RFX) target genes by comparative genomics in Drosophila species2007In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 8, no 9, p. R195-Article in journal (Refereed)
    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.

  • 9.
    Li, C.
    et al.
    Simon Fraser University, Burnaby, BC, Canada.
    Inglis, P. N.
    Simon Fraser University, Burnaby, BC, Canada.
    Leitch, C. C.
    Johns Hopkins University, Baltimore, USA.
    Efimenko, Evgeni
    Södertörn University, School of Life Sciences. Karoliska Institutet.
    Davis, E. E.
    Johns Hopkins University, Baltimore, USA.
    Bialas, N.
    Simon Fraser University, Burnaby, BC, Canada.
    Swoboda, Peter
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Katsanis, N.
    Johns Hopkins University, Baltimore, USA.
    Leroux, M. R.
    Simon Fraser University, Burnaby, BC, Canada.
    Central role for DYF-11/MIP-T3 in assembling kinesin motor-intraflagellar transport complexesManuscript (preprint) (Other academic)
  • 10. Li, Chunmei
    et al.
    Inglis, Peter N.
    Leitch, Carmen C.
    Efimenko, Evgeni
    Södertörn University, School of Life Sciences.
    Zaghloul, Norann A.
    Mok, Calvin A.
    Davis, Erica E.
    Bialas, Nathan J.
    Healey, Michael P.
    Heon, Elise
    Zhen, Mei
    Swoboda, Peter
    Södertörn University, School of Life Sciences.
    Katsanis, Nicholas
    Leroux, Michel R.
    An essential role for DYF-11/MIP-T3 in assembling functional intraflagellar transport complexes2008In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 4, no 3, p. e1000044-Article in journal (Refereed)
    Abstract [en]

    MIP-T3 is a human protein found previously to associate with microtubules and the kinesin-interacting neuronal protein DISC1 ( Disrupted-in-Schizophrenia 1), but whose cellular function(s) remains unknown. Here we demonstrate that the C. elegans MIP-T3 ortholog DYF-11 is an intraflagellar transport (IFT) protein that plays a critical role in assembling functional kinesin motor-IFT particle complexes. We have cloned a loss of function dyf-11 mutant in which several key components of the IFT machinery, including Kinesin-II, as well as IFT subcomplex A and B proteins, fail to enter ciliary axonemes and/or mislocalize, resulting in compromised ciliary structures and sensory functions, and abnormal lipid accumulation. Analyses in different mutant backgrounds further suggest that DYF-11 functions as a novel component of IFT subcomplex B. Consistent with an evolutionarily conserved cilia-associated role, mammalian MIP-T3 localizes to basal bodies and cilia, and zebrafish mipt3 functions synergistically with the Bardet-Biedl syndrome protein Bbs4 to ensure proper gastrulation, a key cilium- and basal body-dependent developmental process. Our findings therefore implicate MIP-T3 in a previously unknown but critical role in cilium biogenesis and further highlight the emerging role of this organelle in vertebrate development.

  • 11. Massinen, Satu
    et al.
    Hokkanen, Marie-Estelle
    Matsson, Hans
    Tammimies, Kristiina
    Tapia-Paez, Isabel
    Dahlstrom-Heuser, Vanina
    Kuja-Panula, Juha
    Burghoorn, Jan
    Södertörn University, School of Life Sciences, Molecular biology.
    Jeppsson, Kristian E.
    Södertörn University, School of Life Sciences, Molecular biology.
    Swoboda, Peter
    Södertörn University, School of Life Sciences, Molecular biology.
    Peyrard-Janvid, Myriam
    Toftgard, Rune
    Castren, Eero
    Kere, Juha
    Increased Expression of the Dyslexia Candidate Gene DCDC2 Affects Length and Signaling of Primary Cilia in Neurons2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, p. e20580-Article in journal (Refereed)
    Abstract [en]

    DCDC2 is one of the candidate susceptibility genes for dyslexia. It belongs to the superfamily of doublecortin domain containing proteins that bind to microtubules, and it has been shown to be involved in neuronal migration. We show that the Dcdc2 protein localizes to the primary cilium in primary rat hippocampal neurons and that it can be found within close proximity to the ciliary kinesin-2 subunit Kif3a. Overexpression of DCDC2 increases ciliary length and activates Shh signaling, whereas downregulation of Dcdc2 expression enhances Wnt signaling, consistent with a functional role in ciliary signaling. Moreover, DCDC2 overexpression in C. elegans causes an abnormal neuronal phenotype that can only be seen in ciliated neurons. Together our results suggest a potential role for DCDC2 in the structure and function of primary cilia.

  • 12.
    Miranda-Vizuete, Antonio
    et al.
    Södertörn University, School of Life Sciences.
    Fierro Gonzalez, Juan Carlos
    Södertörn University, School of Life Sciences.
    Gahmon, Gabriele
    Burghoorn, Jan
    Södertörn University, School of Life Sciences.
    Navas, Plácido
    Swoboda, Peter
    Södertörn University, School of Life Sciences.
    Lifespan decrease in a Caenorhabditis elegans mutant lacking TRX-1, a thioredoxin expressed in ASJ sensory neurons2006In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 580, no 2, p. 484-490Article in journal (Refereed)
    Abstract [en]

    Thioredoxins are a class of small proteins that play a key role in regulating many cellular redox processes. We report here the characterization of the first member of the thioredoxin family in metazoans that is mainly associated with neurons. The Caenorhabditis elegans gene B0228.5 encodes a thioredoxin (TRX-1) that is expressed in ASJ ciliated sensory neurons, and to some extent also in the posterior-most intestinal cells. TRX-1 is active at reducing protein disulfides in the presence of a heterologous thioredoxin reductase. A mutant worm strain carrying a null allele of the trx-1 gene displays a reproducible decrease in both mean and maximum lifespan when compared to wild-type. The identification and characterization of TRX-1 paves the way to use C elegans as an in vivo model to study the role of thioredoxins in lifespan and nervous system physiology and pathology.

  • 13. Rhind, Nicholas
    et al.
    Chen, Zehua
    Yassour, Moran
    Thompson, Dawn A.
    Haas, Brian J.
    Habib, Naomi
    Wapinski, Ilan
    Roy, Sushmita
    Lin, Michael F.
    Heiman, David I.
    Young, Sarah K.
    Furuya, Kanji
    Guo, Yabin
    Pidoux, Alison
    Chen, Huei Mei
    Robbertse, Barbara
    Goldberg, Jonathan M.
    Aoki, Keita
    Bayne, Elizabeth H.
    Berlin, Aaron M.
    Desjardins, Christopher A.
    Dobbs, Edward
    Dukaj, Livio
    Fan, Lin
    FitzGerald, Michael G.
    French, Courtney
    Gujja, Sharvari
    Hansen, Klavs
    Keifenheim, Dan
    Levin, Joshua Z.
    Mosher, Rebecca A.
    Mueller, Carolin A.
    Pfiffner, Jenna
    Priest, Margaret
    Russ, Carsten
    Smialowska, Agata
    Södertörn University, School of Life Sciences, Molecular biology.
    Swoboda, Peter
    Sykes, Sean M.
    Vaughn, Matthew
    Vengrova, Sonya
    Yoder, Ryan
    Zeng, Qiandong
    Allshire, Robin
    Baulcombe, David
    Birren, Bruce W.
    Brown, William
    Ekwall, Karl
    Södertörn University, School of Life Sciences, Molecular biology.
    Kellis, Manolis
    Leatherwood, Janet
    Levin, Henry
    Margalit, Hanah
    Martienssen, Rob
    Nieduszynski, Conrad A.
    Spatafora, Joseph W.
    Friedman, Nir
    Dalgaard, Jacob Z.
    Baumann, Peter
    Niki, Hironori
    Regev, Aviv
    Nusbaum, Chad
    Comparative Functional Genomics of the Fission Yeasts2011In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 332, no 6032, p. 930-936Article in journal (Refereed)
    Abstract [en]

    The fission yeast clade-comprising Schizosaccharomyces pombe, S. octosporus, S. cryophilus, and S. japonicus-occupies the basal branch of Ascomycete fungi and is an important model of eukaryote biology. A comparative annotation of these genomes identified a near extinction of transposons and the associated innovation of transposon-free centromeres. Expression analysis established that meiotic genes are subject to antisense transcription during vegetative growth, which suggests a mechanism for their tight regulation. In addition, trans-acting regulators control new genes within the context of expanded functional modules for meiosis and stress response. Differences in gene content and regulation also explain why, unlike the budding yeast of Saccharomycotina, fission yeasts cannot use ethanol as a primary carbon source. These analyses elucidate the genome structure and gene regulation of fission yeast and provide tools for investigation across the Schizosaccharomyces clade.

  • 14. Schafer, J C
    et al.
    Haycraft, C J
    Thomas, J H
    Yoder, B K
    Swoboda, Peter
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    XBX-1 encodes a dynein light intermediate chain required for retrograde intraflagellar transport and cilia assembly in Caenorhabditis elegans2003In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 14, no 5, p. 2057-2070Article in journal (Refereed)
    Abstract [en]

    Intraflagellar transport (IFT) is a process required for flagella and cilia assembly that describes the dynein and kinesin mediated movement of particles along axonemes that consists of an A and a B complex, defects in which disrupt retrograde and anterograde transport, respectively. Herein, we describe a novel Caenorhabditis elegans gene, xbx-1, that is required for retrograde IFT and shares homology with a mammalian dynein light intermediate chain (D2LIC). xbx-1 expression in ciliated sensory neurons is regulated by the transcription factor DAF-19, as demonstrated previously for genes encoding IFT complex B proteins. XBX-1 localizes to the base of the cilia and undergoes anterograde and retrograde movement along the axoneme. Disruption of xbx-1 results in cilia defects and causes behavioral abnormalities observed in other cilia mutants. Analysis of cilia in xbx-1 mutants reveals that they are shortened and have a bulb like structure in which IFT proteins accumulate. The role of XBX-1 in IFT was further confirmed by analyzing the effect that other IFT mutations have on XBX-1 localization and movement. In contrast to other IFT proteins, retrograde XBX-1 movement was detected in complex A mutants. Our results suggest that the DLIC protein XBX-1 functions together with the CHE-3 dynein in retrograde IFT, downstream of the complex A proteins.

  • 15.
    Senti, Gabriele
    et al.
    Södertörn University, School of Life Sciences.
    Ezcurra, Marina
    Löbner, Jana
    Södertörn University, School of Life Sciences.
    Schafer, William R.
    Swoboda, Peter
    Södertörn University, School of Life Sciences, Molecular biology.
    Worms With a Single Functional Sensory Cilium Generate Proper Neuron-Specific Behavioral Output2009In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 183, no 2, p. 595-605Article in journal (Refereed)
    Abstract [en]

    Studying the development and mechanisms of sensory perception is challenging in organisms with complex neuronal networks. The worm Caenorhabditis elegans possesses a simple neuronal network of 302 neurons that includes 60 ciliated sensory neurons (CSNs) for detecting external sensory input. C. elegans is thus an excellent model in which to study sensory neuron development., function, and behavior. We have generated a genetic rescue system that allows in vivo analyses of isolated CSNs at both cellular and systemic levels. We used the RFX transcription factor DAF-19, a key regulator of ciliogenesis. Mutations in daf-19 result in the complete absence of all sensory cilia and thus of external sensory input. In daf-19 mutants, we used cell-specific rescue of DAF-19 function in selected neurons, thereby generating animals with single, fully functional CSNs. Otherwise and elsewhere these animals are completely devoid of any environmental input through cilia. We demonstrated the rescue of fully functional, single cilia using fluorescent markers, sensory behavioral assays, and calcium imaging. Our technique, functional rescue in single sensory cilia (FRISSC), can thus cell-autonomously and cell-specifically restore the function of single sensory neurons and their ability to respond to sensory input. FRISSC can be adapted to many different CSNs and thus constitutes an excellent tool for studying sensory behaviors, both in single animals and in populations of worms. FRISSC will be Very useful for the molecular dissection of sensory perception in CSNs and for the analysis of the developmental aspects of ciliogenesis.

  • 16.
    Senti, Gabriele
    et al.
    Södertörn University, School of Life Sciences.
    Swoboda, Peter
    Södertörn University, School of Life Sciences.
    Distinct Isoforms of the RFX Transcription Factor DAF-19 Regulate Ciliogenesis and Maintenance of Synaptic Activity2008In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 19, no 12, p. 5517-5528Article in journal (Refereed)
    Abstract [en]

    Neurons form elaborate subcellular structures such as dendrites, axons, cilia, and synapses to receive signals from their environment and to transmit them to the respective target cells. In the worm Caenorhabditis elegans, lack of the RFX transcription factor DAF-19 leads to the absence of cilia normally found on 60 sensory neurons. We now describe and functionally characterize three different isoforms of DAF-19. The short isoform DAF-19C is specifically expressed in ciliated sensory neurons and sufficient to rescue all cilia-related phenotypes of daf-19 mutants. In contrast, the long isoforms DAF-19A/B function in basically all nonciliated neurons. We discovered behavioral and cellular phenotypes in daf-19 mutants that depend on the isoforms daf-19a/b. These novel synaptic maintenance phenotypes are reminiscent of synaptic decline seen in many human neurodegenerative disorders. The C. elegans daf-19 mutant worms can thus serve as a molecular model for the mechanisms of functional neuronal decline.

  • 17.
    Smialowska, Agata
    et al.
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies, Biology. Karolinska instiutet.
    Djupedal, Ingela
    Karolinska instiutet.
    Wang, Jingwen
    Karolinska instiutet.
    Kylsten, Per
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies, Biology.
    Swoboda, Peter
    Karolinska instiutet.
    Ekwall, Karl
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies, Biology. Karolinska instiutet.
    RNAi mediates post-transcriptional repression of gene expression in fission yeast Schizosaccharomyces pombe2014In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 444, no 2, p. 254-259Article in journal (Other academic)
    Abstract [en]

    RNA interference (RNAi) is a gene silencing mechanism conserved from fungi to mammals. Small interfering RNAs are products and mediators of the RNAi pathway and act as specificity factors in recruiting effector complexes. The Schizosaccharomyces pombe genome encodes one of each of the core RNAi proteins, Dicer, Argonaute and RNA-dependent RNA polymerase (dcr1, ago1, rdp1). Even though the function of RNAi in heterochromatin assembly in S. pombe is established, its role in controlling gene expression is elusive. Here, we report the identification of small RNAs mapped anti-sense to protein coding genes in fission yeast. We demonstrate that these genes are up-regulated at the protein level in RNAi mutants, while their mRNA levels are not significantly changed. We show that the repression by RNAi is not a result of heterochromatin formation. Thus, we conclude that RNAi is involved in post-transcriptional gene silencing in S. pombe.

  • 18. Stenvall, Jörgen
    et al.
    Fierro-Gonzalez, Juan Carlos
    Södertörn University, School of Life Sciences, Molecular biology.
    Swoboda, Peter
    Södertörn University, School of Life Sciences, Molecular biology.
    Saamarthy, Karunakar
    Cheng, Qing
    Cacho-Valadez, Briseida
    Arner, Elias S. J.
    Persson, Olof P.
    Miranda-Vizuete, Antonio
    Tuck, Simon
    Selenoprotein TRXR-1 and GSR-1 are essential for removal of old cuticle during molting in Caenorhabditis elegans2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 3, p. 1064-1069Article in journal (Refereed)
    Abstract [en]

    Selenoproteins, in particular thioredoxin reductase, have been implicated in countering oxidative damage occurring during aging but the molecular functions of these proteins have not been extensively investigated in different animal models. Here we demonstrate that TRXR-1 thioredoxin reductase, the sole selenoprotein in Caenorhabditis elegans, does not protect against acute oxidative stress but functions instead together with GSR-1 glutathione reductase to promote the removal of old cuticle during molting. We show that the oxidation state of disulfide groups in the cuticle is tightly regulated during the molting cycle, and that when trxr-1 and gsr-1 function is reduced, disulfide groups in the cuticle remain oxidized. A selenocysteine-to-cysteine TRXR-1 mutant fails to rescue molting defects. Furthermore, worms lacking SELB-1, the C. elegans homolog of Escherichia coli SelB or mammalian EFsec, a translation elongation factor known to be specific for selenocysteine in E. coli, fail to incorporate selenocysteine, and display the same phenotype as those lacking trxr-1. Thus, TRXR-1 function in the reduction of old cuticle is strictly selenocysteine dependent in the nematode. Exogenously supplied reduced glutathione reduces disulfide groups in the cuticle and induces apolysis, the separation of old and new cuticle, strongly suggesting that molting involves the regulated reduction of cuticle components driven by TRXR-1 and GSR-1. Using dauer larvae, we demonstrate that aged worms have a decreased capacity to molt, and decreased expression of GSR-1. Together, our results establish a function for the selenoprotein TRXR-1 and GSR-1 in the removal of old cuticle from the surface of epidermal cells.

  • 19.
    Swoboda, Peter
    Södertörn University, School of Life Sciences.
    Worms with only a single cilium S.: per animal2009In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 126, p. S17-S17Article in journal (Refereed)
  • 20. Winkelbauer, M E
    et al.
    Schafer, J C
    Haycraft, C J
    Swoboda, Peter
    Södertörn University, School of Life Sciences.
    Yoder, B K
    The C-elegans homologs of nephrocystin-1 and nephrocystin-4 are cilia transition zone proteins involved in chemosensory perception2005In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 118, no 23, p. 5575-5587Article in journal (Refereed)
    Abstract [en]

    Nephronophthisis (NPH) is a cystic kidney disorder that causes end-stage renal failure in children. Five nephrocystin (nephrocystin-1 to nephrocystin-5) genes, whose function is disrupted in NPH patients, have been identified and data indicate they form a complex at cell junctions and focal adhesions. More recently, the nephrocystin proteins have also been identified in cilia, as have multiple other cystic kidney disease related proteins. Significant insights into this cilia and cystic kidney disease connection have come from analyses in simpler eukaryotic organisms such as Caenorhabditis elegans. In this regard, we became interested in the C elegans homologs of nephrocystin-1 (nph-1) and nephrocystin-4 (nph-4) from a database screen to identify genes coordinately regulated by the ciliogenic transcription factor DAF-19. Here we show that expression of nph-1 and nph-4 is DAF-19 dependent, that their expression is restricted to ciliated sensory neurons, and that both NPH-1 and NPH-4 concentrate at the transition zones at the base of the cilia, but are not found in the cilium axoneme. In addition, NPH-4 is required for the localization of NPH-1 to this domain. Interestingly, nph-1 or nph-4 mutants have no obvious cilia assembly defects; however, they do have abnormalities in cilia-mediated sensory functions as evidenced by abnormal chemotaxis and lifespan regulation. Our data suggest that rather than having a ciliogenic role, the NPH proteins play an important function as part of the sensory or signaling machinery of this organelle. These findings suggest that the defects in human NPH patients may not be the result of aberrant ciliogenesis but abnormal cilia-sensory functions.

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