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  • 1. Allendorf, Fred
    et al.
    Ryman, Nils
    Stockholm University, Faculty of Science, Department of Zoology.
    The role of genetics in population viability analysis2002In: Population Viability Analysis / [ed] Beissinger,S.R. and McCullough,D.R., Chicago: University of Chicago Press , 2002, p. 50-85Chapter in book (Other academic)
  • 2. Andriamihajarivo, Tefy H.
    et al.
    Razafimandimbison, Sylvain G.
    Stockholm University, Faculty of Science, Department of Botany.
    Karehed, Jesper
    Phyllopentas flava (Rubiaceae), a New Morphologically Heterodistylous and Functionally Dioecious Species from Madagascar2011In: Systematic Botany, ISSN 0363-6445, E-ISSN 1548-2324, Vol. 36, no 4, p. 1024-1027Article in journal (Refereed)
    Abstract [en]

    A new species of the Afro-Malagasy genus Phyllopentas Karehed & B. Bremer, Phyllopentas flava Razafim., T. Andriam. et Karehed, is described and illustrated. This plant is restricted to the Itremo region in southeastern Madagascar and is distinct morphologically from the other species of the genus by its pubescent, narrowly ovate to narrowly elliptic leaves, grey-whitish and thickly hairy midribs and secondary veins on the lower surfaces of leaves, and functionally dioecious and heterodistylous flowers. Summaries of distribution, phenology, habitat, and ecology are given and a conservation assessment is also provided.

  • 3. André, Carl
    et al.
    Larsson, Lena C
    Stockholm University, Faculty of Science, Department of Zoology.
    Laikre, Linda
    Stockholm University, Faculty of Science, Department of Zoology.
    Bekkevold, D
    Brigham, J
    Carvalho, GR
    Dahlgren, TG
    Hutchinson, WF
    Mariani, S
    Mudde, K
    Ruzzante, DE
    Ryman, Nils
    Stockholm University, Faculty of Science, Department of Zoology.
    Detecting population structure in a high gene-flow species, Atlantic herring (Clupea harengus): direct, simultaneous evaluation of neutral vs putatively selected loci2011In: Heredity, ISSN 0018-067X, E-ISSN 1365-2540, Vol. 106, no 2, p. 270-280Article in journal (Refereed)
    Abstract [en]

    In many marine fish species, genetic population structure is typically weak because populations are large, evolutionarily young and have a high potential for gene flow. We tested whether genetic markers influenced by natural selection are more efficient than the presumed neutral genetic markers to detect population structure in Atlantic herring (Clupea harengus), a migratory pelagic species with large effective population sizes. We compared the spatial and temporal patterns of divergence and statistical power of three traditional genetic marker types, microsatellites, allozymes and mitochondrial DNA, with one microsatellite locus, Cpa112, previously shown to be influenced by divergent selection associated with salinity, and one locus located in the major histocompatibility complex class IIA (MHC-IIA) gene, using the same individuals across analyses. Samples were collected in 2002 and 2003 at two locations in the North Sea, one location in the Skagerrak and one location in the low-saline Baltic Sea. Levels of divergence for putatively neutral markers were generally low, with the exception of single outlier locus/sample combinations; microsatellites were the most statistically powerful markers under neutral expectations. We found no evidence of selection acting on the MHC locus. Cpa112, however, was highly divergent in the Baltic samples. Simulations addressing the statistical power for detecting population divergence showed that when using Cpa112 alone, compared with using eight presumed neutral microsatellite loci, sample sizes could be reduced by up to a tenth while still retaining high statistical power. Our results show that the loci influenced by selection can serve as powerful markers for detecting population structure in high gene-flow marine fish species.

  • 4.
    Arcot Jayaram, Satish
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    New roles for apical secretion and extracellular matrix assembly in Drosophila epithelial morphogenesis2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Branched tubular organs, such as the lung and vascular system fulfill the respiratory needs of most animals. Optimal tissue function relies on the uniform sizes and shapes of the constituting branches in each organ. The Drosophila tracheal airways provide a recognized genetic model system for identification and characterization of tube size regulators. We found that the programmed secretion and assembly of the apical extracellular matrix (ECM) is required for the expansion of the trachea and salivary glands (SG) tubes. We have characterized Vermiform (Verm) and Serpentine (Serp), two chitin-binding proteins with predicted polysaccharide deacetylase domains (ChLDs). Verm and Serp mutants show overelongated tubes, suggesting that luminal ECM modification restricts tracheal tube elongation. The luminal deposition of ChLDs, but not other secreted components, depends on paracellular septate junction integrity (SJs) in the tracheal epithelium. Deletion of the deacetylase domain renders Serp-GFP intracellular, arguing that the deacetylase domain harbors uncharacterized secretion signals. To explore this possibility we transferred the deacetylase domain from Serp to Gasp, another tracheal luminal protein, which requires the Emp24 adaptor for ER exit. The Gasp-Deac-GFP chimera was normally secreted in emp24 mutants indicating that the deacetylase domain contains potential ER-exit signals. To identify such signals we characterized conserved sequence motifs in the Serp deacetylase domain. Mutations of the N-glycosylation sites gradually reduced Serp-GFP luminal deposition suggesting that increased glycosylation enhances apical Serp secretion. By contrast, substitutions in three conserved amino acid stretches completely blocked the ER-exit of Serp-GFP. The mutated proteins were N-glycosylated suggesting that the motifs may be involved in a subsequent protein-folding step or facilitate ER exit through interactions with unidentified specific adaptors.

  • 5.
    Barsoum, Emad
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Mating type switching and transcriptional silencing in Kluyveromyces lactis2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    To explore the similarities and differences of regulatory circuits among budding yeasts, we characterized the role of unscheduled meiotic gene expression 6 (UME6) and a novel mating type switching pathway in Kluyveromyces lactis. We found that Ume6 was required for transcriptional silencing of the cryptic mating-type loci HMLα and HMRa. Ume6 acted directly at these loci by binding to the cis-regulatory silencers. Ume6 also served as a block to polyploidy and was required for repression of three meiotic genes, independently of the Rpd3 and Sin3 corepressors.

    Mating type switching from MATα to MATa required the α3 protein. The α3 protein was similar to transposases of the mutator like elements (MULEs). Mutational analysis showed that the DDE-motif in α3, which is conserved in MULEs was necessary for switching. During switching α3 mobilizes from the genome in the form of a DNA circle. The sequences encompassing the α3 gene circle junctions in the MATα locus were essential for switching from MATα to MATa. Switching also required a DNA binding protein, Mating type switch 1 (Mts1), whose binding sites in MATα were important. Expression of Mts1 was repressed in MATa/MATα diploids and by nutrients, limiting switching to haploids in low nutrient conditions.

    In a genetic selection for strains with increased switching rates we found a mutation in the RAS1 gene. By measuring the levels of the MTS1 mRNA and switching rates in ras1, pde2 and msn2 mutant strains we show that mating type switching in K. lactis was regulated by the RAS/cAMP pathway and the transcription factor Msn2. ras1 mutants contained 20-fold higher levels of MTS1 mRNA compared to wild type whereas pde2 and msn2 expressed less MTS1 mRNA and had decreased switching rates. Furthermore we found that MTS1 contained several potential Msn2 binding sites upstream of its ORF. We suggest that these observations explain the nutrient regulation of switching.

  • 6.
    Barsoum, Emad
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Martinez, Paula
    Åström, Stefan U.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    {alpha}3, a transposable element that promotes host sexual reproduction2010In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 24, no 15, p. 33-44Article in journal (Refereed)
    Abstract [en]

    Theoretical models predict that selfish DNA elements require host sex to persist in a population. Therefore, a transposon that induces sex would strongly favor its own spread. We demonstrate that a protein homologous to transposases, called alpha3, was essential for mating type switch in Kluyveromyces lactis. Mutational analysis showed that amino acids conserved among transposases were essential for its function. During switching, sequences in the 5' and 3' flanking regions of the alpha3 gene were joined, forming a DNA circle, showing that alpha3 mobilized from the genome. The sequences encompassing the alpha3 gene circle junctions in the mating type alpha (MATalpha) locus were essential for switching from MATalpha to MATa, suggesting that alpha3 mobilization was a coupled event. Switching also required a DNA-binding protein, Mating type switch 1 (Mts1), whose binding sites in MATalpha were important. Expression of Mts1 was repressed in MATa/MATalpha diploids and by nutrients, limiting switching to haploids in low-nutrient conditions. A hairpin-capped DNA double-strand break (DSB) was observed in the MATa locus in mre11 mutant strains, indicating that mating type switch was induced by MAT-specific DSBs. This study provides empirical evidence for selfish DNA promoting host sexual reproduction by mediating mating type switch.

  • 7.
    Barsoum, Emad
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Sjöstrand, Jimmy O. O.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Åström, Stefan U.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Ume6 is required for the MATa/MATα cellular identity and transcriptional silencing in Kluyveromyces lactis2010In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 184, no 4, p. 999-1011Article in journal (Refereed)
    Abstract [en]

    To explore the similarities and differences of regulatory circuits among budding yeasts, we characterized the role of the unscheduled meiotic gene expression 6 (UME6) gene in Kluyveromyces lactis. We found that Ume6 was required for transcriptional silencing of the cryptic mating-type loci HMLα and HMRa. Chromatin immunoprecipitation (ChIP) suggested that Ume6 acted directly by binding the cis-regulatory silencers of these loci. Unexpectedly, a MATa ume6 strain was mating proficient, whereas a MATα ume6 strain was sterile. This observation was explained by the fact that ume6 derepressed HMLα2 only weakly, but derepressed HMRa1 strongly. Consistently, two a/α-repressed genes (MTS1 and STE4) were repressed in the MATα ume6 strain, but were expressed in the MATa ume6 strain. Surprisingly, ume6 partially suppressed the mating defect of a MATa sir2 strain. MTS1 and STE4 were repressed in the MATa sir2 ume6 double-mutant strain, indicating that the suppression acted downstream of the a1/α2-repressor. We show that both STE12 and the MATa2/HMRa2 genes were overexpressed in the MATa sir2 ume6 strain. Consistent with the idea that this deregulation suppressed the mating defect, ectopic overexpression of Ste12 and a2 in a MATa sir2 strain resulted in efficient mating. In addition, Ume6 served as a block to polyploidy, since ume6/ume6 diploids mated as pseudo a-strains. Finally, Ume6 was required for repression of three meiotic genes, independently of the Rpd3 and Sin3 corepressors.

  • 8.
    Barsoum, Emad
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Åström, Stefan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Regulation of mating type switching in Kluyveromyces lactis by the RAS/cAMP pathway and the transcription factor Msn2Manuscript (preprint) (Other academic)
    Abstract [en]

    We explored the regulation of mating type switching in Kluyveromyces lactis. Using an assay dependent on loss of a URA3 gene inserted into the MATa locus, we determined that the switching rate of a wild type strain grown in rich media was ~6X10-4 events/generation. In a genetic selection for identifying strains with increased switching rates, we found a strain with an insertion in the K. lactis RAS1 gene, encoding a small GTPase with a central role in growth regulation. Compromised Ras1 function leads to a lower cAMP level suggesting a role for cAMP in promoting switching. Consistent with this idea, a strain lacking the PDE2 gene, which encodes an enzyme that degrades cAMP, resulted in decreased switching rates. To explore how cAMP regulated switching, we investigated the transcription of the MTS1 gene, encoding an inducer of switching. The ras1 mutant strain contained 20-fold higher levels of the MTS1 mRNA compared to wild type, but in the pde2 mutant strain MTS1 transcription was repressed 5-fold. In addition, strains lacking the MSN2 gene, which encodes a transcription factor that binds the stress response element (STRE), expressed less MTS1 mRNA and had decreased switching rates. We suggest a model in which nutrient limitation induces switching through cAMP and Msn2-dependent transcriptional induction of the MTS1 gene.

  • 9.
    Beltran-Pardo, Eliana
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonsson, K. Ingemar
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Kristianstad University, Sweden.
    Harms-Ringdahl, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Tolerance to Gamma Radiation in the Tardigrade Hypsibius dujardini from Embryo to Adult Correlate Inversely with Cellular Proliferation2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0133658Article in journal (Refereed)
    Abstract [en]

    Tardigrades are highly tolerant to desiccation and ionizing radiation but the mechanisms of this tolerance are not well understood. In this paper, we report studies on dose responses of adults and eggs of the tardigrade Hypsibius dujardini exposed to gamma radiation. In adults the LD50/48h for survival was estimated at similar to 4200 Gy, and doses higher than 100 Gy reduced both fertility and hatchability of laid eggs drastically. We also evaluated the effect of radiation (doses 50 Gy, 200 Gy, 500 Gy) on eggs in the early and late embryonic stage of development, and observed a reduced hatchability in the early stage, while no effect was found in the late stage of development. Survival of juveniles from irradiated eggs was highly affected by a 500 Gy dose, both in the early and the late stage. Juveniles hatched from eggs irradiated at 50 Gy and 200 Gy developed into adults and produced offspring, but their fertility was reduced compared to the controls. Finally we measured the effect of low temperature during irradiation at 4000 Gy and 4500 Gy on survival in adult tardigrades, and observed a slight delay in the expressed mortality when tardigrades were irradiated on ice. Since H. dujardini is a freshwater tardigrade with lower tolerance to desiccation compared to limno-terrestrial tardigrades, the high radiation tolerance in adults, similar to limno-terrestrial tardigrades, is unexpected and seems to challenge the idea that desiccation and radiation tolerance rely on the same molecular mechanisms. We suggest that the higher radiation tolerance in adults and late stage embryos of H. dujardini (and in other studied tardigrades) compared to early stage embryos may partly be due to limited mitotic activity, since tardigrades have a low degree of somatic cell division (eutely), and dividing cells are known to be more sensitive to radiation.

  • 10.
    Boija, Ann
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Transcriptional and epigenetic control of gene expression in embryo development2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows.

    We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity.

    CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin.

    Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome. CBP is regulating Pol II activity of nearly all expressed genes, however, either recruitment or release of Pol II is the rate-limiting step affected by CBP.

    Taken together, these results reveal mechanistic insights into cell specification and transcriptional control during development.

     

  • 11.
    Boija, Ann
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Dig Bijay, Mahat
    Zare, Aman
    Holmqvist, Per-Henrik
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Philip, Philge
    Meyers, David J.
    Cole, Philip A.
    Lis, John T.
    Stenberg, Per
    Mannervik, Mattias
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    CBP regulates promoter-proximal RNA polymerase IIManuscript (preprint) (Other academic)
  • 12.
    Carter, Sidney D.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Vigasova, Dana
    Chen, Jiang
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Chovanec, Miroslav
    Åström, Stefan U.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nej1 recruits the Srs2 helicase to DNA double-strand breaks and supports repair by a single-strand annealing-like mechanism2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 29, p. 12037-12042Article in journal (Refereed)
    Abstract [en]

    Double-strand breaks (DSBs) represent the most severe DNA lesion a cell can suffer, as they pose the risk of inducing loss of genomic integrity and promote oncogenesis in mammals. Two pathways repair DSBs, nonhomologous end joining (NHEJ) and homologous recombination (HR). With respect to mechanism and genetic requirements, characterization of these pathways has revealed a large degree of functional separation between the two. Nej1 is a cell-type specific regulator essential to NHEJ in Saccharomyces cerevisiae. Srs2 is a DNA helicase with multiple roles in HR. In this study, we show that Nej1 physically interacts with Srs2. Furthermore, mutational analysis of Nej1 suggests that the interaction was strengthened by Dun1-dependent phosphorylation of Nej1 serines 297/298. Srs2 was previously shown to be recruited to replication forks, where it promotes translesion DNA synthesis. We demonstrate that Srs2 was also efficiently recruited to DSBs generated by the HO endonuclease. Additionally, efficient Srs2 recruitment to this DSB was dependent on Nej1, but independent of mechanisms facilitating Srs2 recruitment to replication forks. Functionally, both Nej1 and Srs2 were required for efficient repair of DSBs with 15-bp overhangs, a repair event reminiscent of a specific type of HR called single-strand annealing (SSA). Moreover, absence of Rad51 suppressed the SSA-defect in srs2 and nej1 strains. We suggest a model in which Nej1 recruits Srs2 to DSBs to promote NHEJ/SSA-like repair by dismantling inappropriately formed Rad51 nucleoprotein filaments. This unexpected link between NHEJ and HR components may represent cross-talk between DSB repair pathways to ensure efficient repair.

  • 13.
    Chen, Jiang
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    DNA double-strand break repair in ascomycetes2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Nonhomologous end joining (NHEJ) and homologous recombination (HR) are two pathways for DNA double strand break (DSB) repair. We found that the NHEJ protein Nej1 interacted physically with the HR protein Srs2, which was dependent on phosphorylation of Nej1 by Dun1. Srs2 recruitment to a DSB partly relied on Nej1 and Dun1. Both Nej1 and Srs2 contributed to efficient single strand annealing (SSA). We suggest that Nej1 and Srs2 facilitate SSA-like repair by disassembling Rad51 nucleoprotein filaments.

    Yen1 is a nuclease that can cleave branched recombination intermediates such as Holliday junctions (HJs). We demonstrated that yen1Δ displayed a negative genetic interaction with mus81 and sgs1 mutants. Mus81 and Sgs1 promoted HJ disjoining by alternative routes, explaining the genetic interaction. Interestingly, catalytically inactive Yen1 had residual functions in DNA repair, suggesting that Yen1 also has a structural role. We discovered that Yen1 interacted physically with Uls1 a potential SUMO targeted ubiquitin ligase. The interaction partly depended on SUMO-modification of the carboxyl terminus of Yen1 and consistent with an ubiquitin ligase function for Uls1, absence of Uls1 stabilized Yen1 after extensive DNA damage. In addition, uls1Δ shared several phenotypes with yen1Δ, including negative genetic interactions with Mus81 after DNA damage and in meiosis. We suggest that Yen1 and Uls1 act together in a DNA repair pathway that is responsible for resolving complex repair intermediates in the absence of Mus81.

    We found that phosphorylation of histone H2A serine 129 promoted DSB repair. Moreover, cells lacking acetylation of lysine residues in the histone H3 NH2-terminus was defective for HR. Interestingly; leaving a single lysine residue intact protected cells from DNA damage. These findings indicate that both histone H2A phosphorylation and histone H3 acetylation are important for the efficiency of the HR-pathway probably by increasing the accessibility of chromatin.

  • 14.
    Chen, Jiang
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Bauer, Stefanie
    Åström, Stefan U.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    The helicase/SUMO-targeted ubiquitin ligase Uls1 interacts both physically and functionally with the Holliday junction resolvase Yen1Manuscript (preprint) (Other academic)
    Abstract [en]

    Yen1 is nuclease that can cleave the Holliday junction (HJ), an important DNA intermediate formed during homologous recombination. Here, we show that Yen1 interacts molecularly with Uls1, a SUMO targeted ubiquitin ligase that also belongs to the SWI/SNF-family of DNA-dependent ATPases. We demonstrate that Yen1 is SUMO modified in its carboxyl terminus and that this modification strengthens the interaction between Yen1 and Uls1. Absence of Uls1 increased the steady-state levels of Yen1, but only after extensive DNA damage, suggesting that Uls1 has a role in damage-induced degradation of Yen1. Consistent with a shared role for Uls1 and Yen1, mutations in the two enzymes display similar phenotypes. Both uls1 and yen1 have a negative genetic interaction with the alternative HJ-cleaving nuclease Mus81. This negative genetic interaction is manifested in supersensitivity to DNA damaging agents, but also in a meiotic defect. Neither mus81 uls1 nor mus81 yen1 double mutant diploids can complete meiosis. Moreover, both uls1 and yen1 exacerbates the chromosome mis-segregation phenotype of mus81. However, the mus81 uls1 yen1 triple mutant strain was slightly more sensitive to DNA damage compared to any double mutant combination, indicating that Uls1 and Yen1 also have independent roles in DNA repair. Point mutant alleles of Uls1 (uls1K975R and uls1C1330S/C1333S) that inactivates the ATPase and potential ubiquitin ligase activities are also supersensitive to DNA damage when combined with mus81, indicating that both activities of Uls1 are essential for function. We suggest that Yen1 and Uls1 are involved in an alternative pathway that is responsible for resolving complex DNA repair intermediates in the absence of Mus81.

  • 15.
    Chen, Jiang
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Åström, Stefan U.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    A catalytic and non-catalytic role for the Yen1 nuclease in maintaining genome integrity in Kluyveromyces lactis2012In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 11, no 10, p. 833-843Article in journal (Refereed)
    Abstract [en]

    Yen1 is a nuclease identified in Saccharomyces cerevisiae that cleaves the Holliday junction (HJ) intermediate formed during homologous recombination. Alternative routes to disjoin HJs are performed by the Mus81/Mms4- and Sgs1/Top3/Rmi1-complexes. Here, we investigate the role of the Yen1 protein in the yeast Kluyveromyces lactis. We demonstrate that both yen1 mus81 and yen1 sgs1 double mutants displayed negative genetic interactions in the presence of DNA-damaging chemicals. To test if these phenotypes required the catalytic activity of Yen1, we introduced point mutations targeting the catalytic site of Yen1, which abolished the nuclease activity in vitro. Remarkably, catalytically inactive Yen1 did not exacerbate the hydroxyurea sensitivity of the sgs1Δ strain, which the yen1Δ allele did. In addition, overexpression of catalytically inactive Yen1 partially rescued the DNA damage sensitivity of both mus81 and sgs1 mutant strains albeit less efficiently than WT Yen1. These results suggest that Yen1 serves both a catalytic and non-catalytic role in its redundant function with Mus81 and Sgs1. Diploids lacking Mus81 had a severe defect in sporulation efficiency and crossover frequency, but diploids lacking both Mus81 and Yen1 showed no further reduction in spore formation. Hence, Yen1 had no evident role in meiosis. However, overexpression of WT Yen1, but not catalytically inactive Yen1 partially rescued the crossover defect in mus81/mus81 mutant diploids. Yen1 is a member of the RAD2/XPG-family of nucleases, but genetic analyses revealed no genetic interaction between yen1 and other family members (rad2, exo1 and rad27). In addition, yen1 mutants had normal nonhomologous end-joining efficiency. We discuss the similarities and differences between K. lactis Yen1 and Yen1/GEN1 from other organisms.

  • 16.
    Chen, Jiang
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Åström, Stefan U.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Developmental Biology.
    Acetylation of the histone H3 N-terminus promotes DNA double-strand break repair in Kluyveromyces lactisManuscript (preprint) (Other academic)
    Abstract [en]

    Condensed chromatin hinders proteins from accessing the DNA, hence posing a block to processes like DNA repair. In this study, we investigate how histone modifications influence DNA double-strand break (DSB) repair. We show that blocking phosphorylation of serine 129 of histone H2A impairs DSB-repair, probably by reducing the efficiency of homologous recombination (HR). The lysine residues of histone H3 and H4 are subjected to reversible acetylation and methylation and we exchanged the lysines for either arginine (mimicking non-acetylated lysine) or glutamine (mimicking acetylated lysine). A histone H3 mutant with five N-terminal lysines exchanged for arginine showed reduced gene conversion and perturbed cell cycle progression. Leaving a single lysine residue intact was sufficient for protecting cells from DNA damage. In addition, exchanging the five lysines for glutamine did not result in these defects, indicating that one lysine residue in the histone H3 N-terminus must be acetylated for efficient DSB-repair. We find no evidence for that histone modification reduces the efficiency of nonhomologous end joining. Furthermore, the histone H3 K9, 14, 18, 23, 27R mutation is not defective in transcription of DSB repair genes indicating that the defects we observe in DSB-repair is unlikely to be due to indirect regulatory effects. These findings indicate that both histone H2A phosphorylation and histone H3 acetylation is important for the efficiency of the HR-pathway.

  • 17. Cintron-Colon, Rigo
    et al.
    Sanchez-Alavez, Manuel
    Nguyen, William
    Mori, Simone
    Gonzalez-Rivera, Ruben
    Lien, Tiffany
    Bartfai, Tamas
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Aid, Saba
    Francois, Jean-Christophe
    Holzenbergerf, Martin
    Conti, Bruno
    Insulin-like growth factor 1 receptor regulates hypothermia during calorie restriction2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 36, p. 9731-9736Article in journal (Refereed)
    Abstract [en]

    When food resources are scarce, endothermic animals can lower core body temperature (Tb). This phenomenon is believed to be part of an adaptive mechanism that may have evolved to conserve energy until more food becomes available. Here, we found in the mouse that the insulin-like growth factor 1 receptor (IGF-1R) controls this response in the central nervous system. Pharmacological or genetic inhibition of IGF-1R enhanced the reduction of temperature and of energy expenditure during calorie restriction. Full blockade of IGF-1R affected female and male mice similarly. In contrast, genetic IGF-1R dosage was effective only in females, where it also induced transient and estrusspecific hypothermia in animals fed ad libitum. These effects were regulated in the brain, as only central, not peripheral, pharmacological activation of IGF-1R prevented hypothermia during calorie restriction. Targeted IGF-1R knockout selectively in forebrain neurons revealed that IGF signaling also modulates calorie restriction-dependent Tb regulation in regions rostral of the canonical hypothalamic nuclei involved in controlling body temperature. In aggregate, these data identify central IGF-1R as a mediator of the integration of nutrient and temperature homeostasis. They also show that calorie restriction, IGF-1R signaling, and body temperature, three of the main regulators of metabolism, aging, and longevity, are components of the same pathway.

  • 18.
    Crona, Filip
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Regulators of chromatin and transcription in Drosophila2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Development of multicellular organisms is achieved by organized temporal and spatial patterns of gene expression leading to cell differentiation. Chromatin regulators control how the DNA is utilized by altering access of proteins to DNA and thereby function as co-factors in transcription. Gene regulation also involves co-factors interacting with transcription factors at regulatory sequences of DNA. In this thesis, we have studied the in vivo role of three co-factors, CBP, dKDM4A and Brakeless, in regulating chromatin and transcription using Drosophila melanogaster. The CREB binding protein (CBP) belongs to histone acetyl transferases (HATs) and facilitates gene activation by many transcription factors. Our work has demonstrated that CBP occupies the genome preferentially together with Rel and Smad proteins controlling dorsal-ventral patterning in the Drosophila embryo. CBP occupancy generally correlates with gene expression but also occurs at silent genes without resulting in histone acetylation. KDM4A belongs to a family of JmjC domain proteins and demethylates H3K36me3, a histone modification enriched in the 3’end of active genes. We generated dKDM4A mutants with a global elevation of H3K36me3 levels and identify mis-regulated genes in first instar larvae. The data indicate that dKDM4A regulates some genes by mechanisms that do not involve H3K36 methylation. Further, over-expression of dKDM4A result in male lethality and globally reduced H3K36me3 levels, indicating impaired dosage compensation of the X-chromosome. Brakeless is a conserved co-factor participating in several important processes during development. We generated mutant brakeless embryos and identify direct genomic targets of Brakeless. To our surprise, Brakeless behaves as a direct activator for some genes but repressor in other cases. We also identify an interaction of Brakeless with the Mediator subunit Med19. In summary, these studies reveal unexpected roles for co-regulators in Drosophila development. The HAT CBP can bind silent genes without leading to histone acetylation. Brakeless has the ability to function both as a direct activator and repressor of transcription.

  • 19.
    Crona, Filip
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Dahlberg, Olle
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Lundberg, Lina E.
    Larsson, Jan
    Mannervik, Mattias
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Gene regulation by the lysine demethylase KDM4A in Drosophila2013In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 373, no 2, p. 453-463Article in journal (Refereed)
    Abstract [en]

    Lysine methylation of histones is associated with both transcriptionally active chromatin and with silent chromatin, depending on what residue is modified. Histone methyltransferases and demethylases ensure that histone methylations are dynamic and can vary depending on cell cycle- or developmental stage. KDM4A demethylates H3K36me3, a modification enriched in the 3' end of active genes. The genomic targets and the role of KDM4 proteins in development remain largely unknown. We therefore generated KDM4A mutant Drosophila, and identified 99 mis-regulated genes in first instar larvae. Around half of these genes were down-regulated and the other half up-regulated in dKDM4A mutants. Although heterochromatin protein 1a (HP1a) can stimulate dKDM4A demethylase activity in vitro, we find that they antagonize each other in control of dKDM4A-regulated genes. Appropriate expression levels for some dKDM4A-regulated genes rely on the demethylase activity of dKDM4A, whereas others do not. Surprisingly, although highly expressed, many demethylase-dependent and independent genes are devoid of H3K36me3 in wild-type as well as in dKDM4A mutant larvae, suggesting that some of the most strongly affected genes in dKDM4A mutant animals are not regulated by H3K36 methylation. By contrast, dKDM4A over-expression results in a global decrease in H3K36me3 levels and male lethality, which might be caused by impaired dosage compensation. Our results show that a modest increase in global H3K36me3 levels is compatible with viability, fertility, and the expression of most genes, whereas decreased H3K36me3 levels are detrimental in males.

  • 20.
    Crona, Filip
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Singla, Bhumica
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Holmqvist, Per-Henrik
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Norberg, Helin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mannervik, Mattias
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fantur, Katrin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Brakeless can directly activate and repress trancription in early Drosophila embryosManuscript (preprint) (Other academic)
    Abstract [en]

    The Brakeless protein performs many important functions during development in Drosophila, but how it controls gene expression is not understood. We previously showed that Brakeless can function as a transcriptional co-repressor. In this work, we perform transcriptional profiling of brakeless mutant embryos. Unexpectedly, the majority of target genes are down-regulated in brakeless mutants. We demonstrate that genomic regions in close proximity to some of the affected genes are occupied by Brakeless, that over-expression of Brakeless causes a reciprocal effect on expression of these genes, and that the activator function of Brakeless is intact when an activation domain is fused to Brakeless. By contrast, Brakeless repressor function is neutralized by the activation domain. Together, this shows that Brakeless can both repress and activate gene expression. To identify protein interactions that result in gene repression or activation, a yeast two-hybrid screen was performed. We find that the Mediator complex subunit Med19 interacts with an evolutionarily conserved part of Brakeless. Interestingly, down-regulated but not up-regulated Brakeless target genes are also affected in Med19-depleted embryos. Our data provide support for a Brakeless activator function that regulates transcription by interacting with Med19.

  • 21.
    Dahlberg, Olle
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Gene regulation during development by chromatin and the Super Elongation Complex2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Developmental processes are carefully controlled at the level of transcription to ensure that the fertilized egg develops into an adult organism. The mechanisms that controls transcription of protein-coding genes ultimately ensure that the Pol II machine synthesizes mRNA from the correct set of genes in every cell type. Transcriptional control involves Pol II recruitment as well as transcriptional elongation. Recent genome-wide studies shows that recruitment of Pol II is often followed by an intermediate step where Pol II is halted in a promoter-proximal paused configuration. The release of Pol II from promoter-proximal pausing is thus an additional and commonly occurring mechanism in metazoan gene regulation. The serine kinase P-TEFb is part of the Super Elongation Complex that regulates the release of paused Pol II into productive elongation. However, little is known about the role of P-TEFb mediated gene expression in development. We have investigated the function of P-TEFb in early Drosophila embryogenesis and find that P-TEFb and other Super Elongation Complex subunits are critical for activation of the most early expressed genes. We demonstrate an unexpected function for Super Elongation Complex in activation of genes with non-paused Pol II. Furthermore, the Super Elongation Complex shares phenotypes with subunits of the Mediator complex to control the activation of essential developmental genes. This raises the possibility that the Super Elongation Complex has an unappreciated role in the recruitment of Pol II to promoters. The unique chromatin landscape of each cell type is comprised of post-translational chromatin modifications such as histone methylations and acetylations. To study the function of histone modifications during development, we depleted the histone demethylase KDM4A in Drosophila to evaluate the role of KDM4A and histone H3 lysine 36 trimethylation (H3K36me3) in gene regulation. We find that KDM4A has a male-specific function and regulates gene expression both by catalytic-dependent and independent mechanisms. Furthermore, we used histone replacement to investigate the direct role of H3K14 acetylation in a multicellular organism. We show that H3K14 acetylation is essential for development, but is not cell lethal, suggesting that H3K14 acetylation has a critical role in developmental gene regulation. This work expands our knowledge of the mechanisms that precisely controls gene regulation and transcription, and in addition highlights the complexity of metazoan development.

  • 22.
    Dai, Qi
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Chromatin regulators and transcriptional control of Drosophila development2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The development of a multicellular organism is programmed by complex patterns of gene expression. In eukaryotic cells, genes are packaged by histone proteins into chromatin. Chromatin regulators often function as transcription co-factors.

    In this study, we have investigated the function of four co-factors, dAda2b, Reptin, Ebi and Brakeless during development of the fruit fly Drosophila melanogaster. dAda2b and Reptin belong to histone acetyl transferase (HAT) complexes, a SAGA-like complex and the Tip60 complex, respectively. We generated dAda2b mutants and found that lack of dAda2b strongly affects global histone acetylation and viability. We further propose that Ada2 may be involved in DNA repair. Our studies revealed new roles of Reptin and other Tip60 complex components in Polycomb Group mediated repression and heterochromatin formation, thereby promoting generation of silent chromatin.

    During embryogenesis, transcriptional repressors establish localized and tissue-specific patterns of gene expression. In this thesis, we identified two novel co-repressors in the early embryo, Ebi and Brakeless. Ebi genetically and physically interacts with the Snail repressor. The Ebi-interaction motif in the Snail protein is essential for Snail function in vivo and is evolutionarily conserved in insects. We further demonstrated that Ebi associates with histone deacetylase 3 (HDAC3) and that histone deacetylation is part of the mechanism by which Snail mediates transcriptional repression.

    We isolated Brakeless in a genetic screen for novel regulators of gene expression during embryogenesis. We found that mutation of brakeless impairs function of the Tailless repressor. Brakeless associates with Atrophin, another Tailless corepressor, and they function together in Tailless-mediated repression.

    In summary, transcription co-factors, including chromatin regulators, are selectively required in distinct processes during development.

  • 23.
    Enquist, Magnus
    et al.
    Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution. Stockholm University, Faculty of Science, Department of Zoology.
    Aronsson, Hanna
    Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution. Stockholm University, Faculty of Science, Department of Zoology.
    Ghirlanda, Stefano
    Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution.
    Jansson, Liselott
    Stockholm University, Faculty of Science, Department of Zoology. Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution.
    Jannini, Emmanuele A.
    Exposure to Mother's Pregnancy and Lactation in Infancy is Associated with Sexual Attraction to Pregnancy and Lactation in Adulthood2011In: Journal of Sexual Medicine, ISSN 1743-6095, E-ISSN 1743-6109, Vol. 8, no 1, p. 140-147Article in journal (Refereed)
    Abstract [en]

    Introduction.  Several theories, including psychodynamic theories, sexual imprinting and early conditioning have been formulated to explain sexual development. Empirical data, however, remain insufficient for a thorough evaluation of these theories.

    Aim.  In this study, we test the hypothesis that a critical period exists for the acquisition of sexual preferences, as suggested by empirical findings in birds and mammals (sexual imprinting).

    Methods.  An Internet questionnaire was used.

    Main Outcome Measures.  We gather data from individuals with a sexual preference for pregnant and/or lactating women, under the hypothesis that pregnancy or lactation may become sexually attractive in adulthood following an exposure to pregnant or lactating women in infancy.

    Results.  We find that these preferences are more common in older siblings, i.e., in individuals who have been exposed to more maternal pregnancy and lactation. This result is independent of respondent and sibling sex. In addition, only maternal pregnancies and lactations experienced between 1.5 and 5 years of age are associated with the preferences.

    Conclusions.  We discuss our findings in relation to theories of sexual development and to earlier reports of birth order effects on sexual behavior. We suggest that this age range may constitute a sensitive period for the acquisition of sexual preferences.

  • 24.
    Friberg, Magne
    et al.
    Stockholm University, Faculty of Science, Department of Zoology. Uppsala universitet.
    Leimar, Olof
    Stockholm University, Faculty of Science, Department of Zoology.
    Wiklund, Christer
    Stockholm University, Faculty of Science, Department of Zoology.
    Heterospecific courtship, minority effects and niche separation between cryptic butterfly species2013In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 26, no 5, p. 971-979Article in journal (Refereed)
    Abstract [en]

    Species interacting in varied ecological conditions often evolve in different directions in different local populations. The butterflies of the cryptic Leptidea complex are sympatrically distributed in different combinations across their Eurasian range. Interestingly, the same species is a habitat generalist in some regions and a habitat specialist in others, where a sibling species has the habitat generalist role. Previous studies suggest that this geographically variable niche divergence is generated by local processes in different contact zones. By varying the absolute and relative densities of Leptidea sinapis and Leptidea juvernica in large outdoor cages, we show that female mating success is unaffected by conspecific density, but strongly negatively affected by the density of the other species. Whereas 80% of the females mated when a conspecific couple was alone in a cage, less than 10% mated when the single couple shared the cage with five pairs of the other species. The heterospecific courtships can thus affect the population fitness, and for the species in the local minority, the suitability of a habitat is likely to depend on the presence or absence of the locally interacting species. If the local relative abundance of the different species depends on the colonization order, priority effects might determine the ecological roles of interacting species in this system.

  • 25.
    Friberg, Magne
    et al.
    Stockholm University, Faculty of Science, Department of Zoology. Evolutionär ekologi.
    Wiklund, Christer
    Stockholm University, Faculty of Science, Department of Zoology. Evolutionär ekologi.
    Generation-dependent female choice: behavioral polyphenism in a bivoltine butterfly2007In: Behavioral Ecology, ISSN 1045-2249, Vol. 18, no 4, p. 758-763Article in journal (Refereed)
    Abstract [en]

    Climatic and biotic circumstances vary as seasons shift, and different cohorts of multivoltine species are likely subjected to different selection regimes. The bivoltine butterfly Leptidea reali (Re´al’s wood white; Lepidoptera: Pieridae) appears during May and June in central Sweden and has a partial second generation in late July. We manipulated both generations to appear simultaneously and performed laboratory mating experiments that showed the presence of a behavioral polyphenism in mating propensity, which is induced during the developmental stages. Females of the summer generation expressed higher mating propensities than spring generation females. Spring females showed an increase in mating propensity with increasing age, whereas summer females accepted most matings already when they were only 1 or 2 days old. It is likely that larval time constraints, a lower abundance of males and a lower risk of accepting a male of their univoltine sister species Leptidea sinapis (wood white), have relaxed selection on mate discrimination among summer generation females. A major challenge for future research is to further investigate the developmental pathways causing the polyphenism and the adaptive implications of cohort dependent behaviors.

  • 26.
    Goodman, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS).
    Koupil, Ilona
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS).
    Lawson, David W.
    Low fertility increases descendant socioeconomic position but reduces long-term fitness in a modern post-industrial society.2012In: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 279, no 1746, p. 4342-4351Article in journal (Refereed)
    Abstract [en]

    Adaptive accounts of modern low human fertility argue that small family size maximizes the inheritance of socioeconomic resources across generations and may consequently increase long-term fitness. This study explores the long-term impacts of fertility and socioeconomic position (SEP) on multiple dimensions of descendant success in a unique Swedish cohort of 14 000 individuals born during 1915-1929. We show that low fertility and high SEP predict increased descendant socioeconomic success across four generations. Furthermore, these effects are multiplicative, with the greatest benefits of low fertility observed when SEP is high. Low fertility and high SEP do not, however, predict increased descendant reproductive success. Our results are therefore consistent with the idea that modern fertility limitation represents a strategic response to the local costs of rearing socioeconomically competitive offspring, but contradict adaptive models suggesting that it maximizes long-term fitness. This indicates a conflict in modern societies between behaviours promoting socioeconomic versus biological success. This study also makes a methodological contribution, demonstrating that the number of offspring strongly predicts long-term fitness and thereby validating use of fertility data to estimate current selective pressures in modern populations. Finally, our findings highlight that differences in fertility and SEP can have important long-term effects on the persistence of social inequalities across generations.

  • 27.
    Hauptmann, Giselbert
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Söll, Iris
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Krautz, Robert
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Multi-target Chromogenic Whole-mount In Situ Hybridization for Comparing Gene Expression Domains in Drosophila Embryos2016In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 107, article id e53830Article in journal (Refereed)
    Abstract [en]

    To analyze gene regulatory networks active during embryonic development and organogenesis it is essential to precisely define how the different genes are expressed in spatial relation to each other in situ. Multi-target chromogenic whole-mount in situ hybridization (MC-WISH) greatly facilitates the instant comparison of gene expression patterns, as it allows distinctive visualization of different mRNA species in contrasting colors in the same sample specimen. This provides the possibility to relate gene expression domains topographically to each other with high accuracy and to define unique and overlapping expression sites. In the presented protocol, we describe a MC-WISH procedure for comparing mRNA expression patterns of different genes in Drosophila embryos. Up to three RNA probes, each specific for another gene and labeled by a different hapten, are simultaneously hybridized to the embryo samples and subsequently detected by alkaline phosphatase-based colorimetric immunohistochemistry. The described procedure is detailed here for Drosophila, but works equally well with zebrafish embryos.

  • 28.
    Hedengren Olcott, Marika
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Relish and the Regulation of Antimicrobial Peptides in Drosophila melanogaster2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The fruit fly Drosophila melanogaster has been a powerful model system in which to study the immune response. When microorganisms breach the mechanical barrier of the insect, phagocytosing cells and a battery of induced antimicrobial molecules rapidly attack them. These antimicrobial peptides can reach micromolar concentrations within a few hours. This immediate response is reminiscent of the mammalian innate immune response and utilizes transcription factors of the NF-κB family.

    We have generated loss-of-function mutants of the NF-κB-like transcription factor Relish in order to investigate Relish's role in the Drosophila immune response to microbes. Relish mutant flies have a severely impaired immune response to Gram-negative (G-) bacteria and some Gram-positive (G+) bacteria and fungi and succumb to an otherwise harmless infection. The main reason for the high susceptibility to infection is that these mutant flies fail to induce the antimicrobial peptide genes. The cellular responses appear to be normal.

    Relish is retained in the cytoplasm in an inactive state. We designed a set of expression plasmids to investigate the requirements for activation of Relish in a hemocyte cell line after stimulation with bacterial lipopolysaccharide. Signal-induced phosphorylation of Relish followed by endoproteolytic processing at the caspase-like target motif in the linker region released the inhibitory ankyrin-repeat (ANK) domain from the DNA binding Rel homology domain (RHD). Separation from the ANK domain allowed the RHD to move into the nucleus and initiate transcription of target genes like those that encode the inducible antimicrobial peptides, likely by binding to κB-like sites in the promoter region.

    By studying the immune response of the Relish mutant flies in combination with mutants for another NF-κB-like protein, Dorsal-related immunity factor (Dif), we found that the Drosophila immune system can distinguish between various microbes and generate a differential response by activating the Toll/Dif and Imd/Relish pathways. The recognition of foreign microorganisms is believed to occur through pattern recognition receptors (PRRs) that have affinity for selective pathogen-associated molecular patterns (PAMPs). We found that the Drosophila PRRs can recognize G- bacteria as a group. Interestingly, the PRRs are specific enough to distinguish between peptidoglycans from G+ bacteria such as Micrococcus luteus and Bacillus megaterium and fungal PAMPs from Beauveria bassiana and Geotrichum candidum.

    This thesis also investigates the expression of the antimicrobial peptide genes, Diptericin B and Attacin C, and the putative intracellular antimicrobial peptide gene Attacin D, and explores a potential evolutionary link between them.

  • 29.
    Hemphälä, Johanna
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Genetic dissection of tubulogenesis in the Drosophila trachea2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The formation of branched tubular organs, such as the mammalian lung kidney and vascular system, is an essential process in animal development. The Drosophila tracheal (respiratory) system provides a genetic model system to study the highly ordered process of branch outgrowth and fusion required to form continuous tubular networks.

    In a transposon mutagenesis screen we identified several genes involved in the different steps of tracheal network formation, including branch fusion. We initially studied the differentiation of the fusion cell in the dorsal branches (DBs). The DBs consists of 5-6 cells, one of which acquires the fusion cell fate. Our results point to a role for Decapentaplegic (Dpp), the Drosophila homolog of transforming growth factor-b (TGFb), in inducing the DB fusion cells fate. The Delta/Notch pathway is then required to select and restrict the fusion cell fate to a single cell in the DBs.

    After the outgrowth and fusion of tracheal branches, the constituent tubes acquire distinct size and shapes to generate a functional tubular tissue. We have found that a mutation in the grainyhead (grh) gene cause the branches to elongate excessively. Cellular and ultrastructural analyses showed that this phenotype was generated by apical cell membrane overgrowth. It was further shown that the activity of Grh is modulated by Branchless, the key regulator of branch outgrowth. Mutations in the Na/K ATPase a subunit (ATP a) and the fasiclin II (fasII) genes, cause similar elongated tracheal tubes as the ones found in grh mutants, but instead these mutations affect the lateral subcellular compartment, independently of the function of Grh in the apical cell domain.

    In a search for downstream effectors of Grh, we found the krotzkopf verkehrt (kkv) gene, encoding a Drosophila chitin synthase. Analysis of kkv mutants suggests that a chitinous intralumenal cable, lacking in kkv embryos, is essential for the tracheal tubes to attain their correct length and diameter. The composition of the chitinous filament is also affected in mutants of various septate junction components, indicating that their tube size defects are at least in part caused by an inability to correctly assemble the intralumenal chitinous matrix formed by Kkv.

  • 30.
    Holmqvist, Per-Henrik
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Boija, Ann
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Philip, Philge
    Crona, Filip
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Stenberg, Per
    Mannervik, Mattias
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Preferential Genome Targeting of the CBP Co-Activator by Rel and Smad Proteins in Early Drosophila melanogaster Embryos2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 6, article id e1002769Article in journal (Refereed)
    Abstract [en]

    CBP and the related p300 protein are widely used transcriptional co-activators in metazoans that interact with multiple transcription factors. Whether CBP/p300 occupies the genome equally with all factors or preferentially binds together with some factors is not known. We therefore compared Drosophila melanogaster CBP (nejire) ChIP-seq peaks with regions bound by 40 different transcription factors in early embryos, and we found high co-occupancy with the Rel-family protein Dorsal. Dorsal is required for CBP occupancy in the embryo, but only at regions where few other factors are present. CBP peaks in mutant embryos lacking nuclear Dorsal are best correlated with TGF-beta/Dpp-signaling and Smad-protein binding. Differences in CBP occupancy in mutant embryos reflect gene expression changes genome-wide, but CBP also occupies some non-expressed genes. The presence of CBP at silent genes does not result in histone acetylation. We find that Polycomb-repressed H3K27me3 chromatin does not preclude CBP binding, but restricts histone acetylation at CBP-bound genomic sites. We conclude that CBP occupancy in Drosophila embryos preferentially overlaps factors controlling dorsoventral patterning and that CBP binds silent genes without causing histone hyperacetylation.

  • 31.
    Holmqvist, Per-Henrik
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Mannervik, Mattias
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Genomic occupancy of the transcriptional co-activators p300 and CBP.2012In: Transcription, ISSN 2154-1272, Vol. 4, no 1, p. 18-23Article in journal (Refereed)
    Abstract [en]

    The p300 and CBP co-activators are histone acetylases and central regulators of transcription in metazoans. The genomic occupancy of p300/CBP detected by ChIP-seq experiments can be used to identify transcriptional enhancers. However, studies in Drosophila embryos suggest that there is a preference for some transcription factors in directing p300/CBP to the genome. Although p300/CBP occupancy in general correlates with gene activation, they can also be found at silent genomic regions, which does not result in histone acetylation. Polycomb-mediated H3K27me3 is associated with repression, but does not preclude p300/CBP binding. An antagonism between H3K27ac and H3K27me3 indicates that p300/CBP may be involved in switching between repressed and active chromatin states.

  • 32.
    Hosono, Chie
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Matsuda, Ryo
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Adryan, Boris
    Samakovlis, Christos
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Giessen, Germany.
    Transient junction anisotropies adjust 3-dimensional cell polarization to tissue geometryManuscript (preprint) (Other academic)
  • 33. Hughes, Terry P.
    et al.
    Carpenter, Stephen
    Rockström, Johan
    Stockholm University, Stockholm Resilience Centre, Stockholm Environment Institute.
    Scheffer, Marten
    Walker, Brian
    Multiscale regime shifts and planetary boundaries2013In: Trends in Ecology & Evolution, ISSN 0169-5347, E-ISSN 1872-8383, Vol. 28, no 7, p. 389-395Article in journal (Refereed)
    Abstract [en]

    Life on Earth has repeatedly displayed abrupt and massive changes in the past, and there is no reason to expect that comparable planetary-scale regime shifts will not continue in the future. Different lines of evidence indicate that regime shifts occur when the climate or biosphere transgresses a tipping point. Whether human activities will trigger such a global event in the near future is uncertain, due to critical knowledge gaps. In particular, we lack understanding of how regime shifts propagate across scales, and whether local or regional tipping points can lead to global transitions. The ongoing disruption of ecosystems and climate, combined with unprecedented breakdown of isolation by human migration and trade, highlights the need to operate within safe planetary boundaries.

  • 34.
    Janz, Niklas
    et al.
    Stockholm University, Faculty of Science, Department of Zoology. Stockholm University, Faculty of Science, Department of Zoology, Department of Animal Ecology. Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution.
    Söderlind, Lina
    Stockholm University, Faculty of Science, Department of Zoology. Stockholm University, Faculty of Science, Department of Zoology, Department of Animal Ecology.
    Nylin, Sören
    Stockholm University, Faculty of Science, Department of Zoology. Stockholm University, Faculty of Science, Department of Zoology, Department of Animal Ecology.
    No effect of larval experience on adult host preferences in Polygonia c-album (Lepidoptera: Nymphalidae): on the persistence of Hopkins' host selection principle2009In: Ecological Entomology, ISSN 0307-6946, E-ISSN 1365-2311, Vol. 34, no 1, p. 50-57Article in journal (Refereed)
    Abstract [en]

    1. The possible effect of juvenile imprinting or 'chemical legacy' on the subsequent oviposition - often called the 'Hopkins' host selection principle' - has been a controversial but recurrent theme in the literature on host-plant preference. While it appears possible in principle, experimental support for the hypothesis is equivocal. The present study points out that it is also important to consider its theoretical implications, and asks under what circumstances, if any, it should be favoured by natural selection.

    2. Following this reasoning, it is predicted that host preference in the polyphagous butterfly Polygonia c-album L. (Lepidoptera, Nymphalidae) should not be influenced by larval environment. This was tested by rearing larvae on three natural host plants: the high-ranked Urtica dioica and the medium-ranked Salix cinerea and Ribes uva-crispa, and exposing the naive females to oviposition choices involving the same set of plants.

    3. It was found that larval host plant had no effect on oviposition decisions of the adult female. Hence, the Hopkins' host selection principle does not seem to be applicable in this species.

    4. Based on recent insights on how accuracy of environmental versus genetic information should affect the control of developmental switches, the conditions that could favour the use of juvenile cues in oviposition decisions are discussed. Although the Hopkins' host selection hypothesis cannot be completely ruled out, we argue that the circumstances required for it to be adaptive are so specific that it should not be invoked as a general hypothesis for host selection in plant-feeding insects.

     

  • 35.
    Jayaram, Satish Arcot
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Senti, Kirsten-André
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Tiklová, Katarina
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Tsarouhas, Vasilios
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Hemphälä, Johanna
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Samakovlis, Christos
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    COPI Vesicle Transport Is a Common Requirement for Tube Expansion in Drosophila2008In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 09 AprArticle in journal (Refereed)
    Abstract [en]

    Background Tube expansion defects like stenoses and atresias cause devastating human diseases. Luminal expansion during organogenesis begins to be elucidated in several systems but we still lack a mechanistic view of the process in many organs. The Drosophila tracheal respiratory system provides an amenable model to study tube size regulation. In the trachea, COPII anterograde transport of luminal proteins is required for extracellular matrix assembly and the concurrent tube expansion.

    Principal Findings We identified and analyzed Drosophila COPI retrograde transport mutants with narrow tracheal tubes. γCOP mutants fail to efficiently secrete luminal components and assemble the luminal chitinous matrix during tracheal tube expansion. Likewise, tube extension is defective in salivary glands, where it also coincides with a failure in the luminal deposition and assembly of a distinct, transient intraluminal matrix. Drosophila γCOP colocalizes with cis-Golgi markers and in γCOP mutant embryos the ER and Golgi structures are severely disrupted. Analysis of γCOP and Sar1 double mutants suggests that bidirectional ER-Golgi traffic maintains the ER and Golgi compartments and is required for secretion and assembly of luminal matrixes during tube expansion.

    Conclusions/Significance Our results demonstrate the function of COPI components in organ morphogenesis and highlight the common role of apical secretion and assembly of transient organotypic matrices in tube expansion. Intraluminal matrices have been detected in the notochord of ascidians and zebrafish COPI mutants show defects in notochord expansion. Thus, the programmed deposition and growth of distinct luminal molds may provide distending forces during tube expansion in diverse organs.

  • 36. Jones, Sarah
    et al.
    Lukanowska, Monika
    Suhorutsenko, Julia
    Oxenham, Senga
    Barratt, Christopher
    Publicover, Steven
    Copolovici, Dana Maria
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Howl, John
    Intracellular translocation and differential accumulation of cell-penetrating peptides in bovine spermatozoa: evaluation of efficient delivery vectors that do not compromise human sperm motility2013In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 28, no 7, p. 1874-1889Article in journal (Refereed)
    Abstract [en]

    Do cell penetrating peptides (CPPs) translocate into spermatozoa and, if so, could they be utilized to deliver a much larger protein cargo? Chemically diverse polycationic CPPs rapidly and efficiently translocate into spermatozoa. They exhibit differential accumulation within intracellular compartments without detrimental influences upon cellular viability or motility but they are relatively ineffective in transporting larger proteins. Endocytosis, the prevalent route of protein internalization into eukaryotic cells, is severely compromised in mature spermatozoa. Thus, the translocation of many bioactive agents into sperm is relatively inefficient. However, the delivery of bioactive moieties into mature spermatozoa could be significantly improved by the identification and utility of an efficient and inert vectorial delivery technology. CPP translocation efficacies, their subsequent differential intracellular distribution and the influence of peptides upon viability were determined in bovine spermatozoa. Temporal analyses of sperm motility in the presence of exogenously CPPs utilized normozoospermic human donor samples. CPPs were prepared by manual, automated and microwave-enhanced solid phase synthesis. Confocal fluorescence microscopy determined the intracellular distribution of rhodamine-conjugated CPPs in spermatozoa. Quantitative uptake and kinetic analyses compared the translocation efficacies of chemically diverse CPPs and conjugates of biotinylated CPPs and avidin. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) conversion assays were employed to analyse the influence of CPPs upon sperm cell viability and sperm class assays determined the impact of CPPs on motility in capacitated and non-capacitated human samples. Chemically heterogeneous CPPs readily translocated into sperm to accumulate within discrete intracellular compartments. Mitoparan (INLKKLAKL(Aib)KKIL), for example, specifically accumulated within the mitochondria located in the sperm midpiece. The unique plasma membrane composition of sperm is a critical factor that directly influences the uptake efficacy of structurally diverse CPPs. No correlations in efficacies were observed when comparing CPP uptake into sperm with either uptake into fibroblasts or direct translocation across a phosphatidylcholine membrane. These comparative investigations identified C105Y (CSIPPEVKFNKPFVYLI) as a most efficient pharmacokinetic modifier for general applications in sperm biology. Significantly, CPP uptake induced no detrimental influence upon either bovine sperm viability or the motility of human sperm. As a consequence of the lack of endocytotic machinery, the CPP-mediated delivery of much larger protein complexes into sperm is relatively inefficient when compared with the similar process in fibroblasts. It is possible that some CPPs could directly influence aspects of sperm biology and physiology that were not analysed in this study. CPP technologies have significant potential to deliver selected bioactive moieties and so could modulate the biology and physiology of human sperm biology both prior- and post-fertilization. We are pleased to acknowledge financial support from the following sources: the Wellcome Trust, TENOVUS (Scotland), University of Dundee, Medical Research Council, NHS Tayside and Scottish Enterprise and the Research Institute in Healthcare Science, University of Wolverhampton. No conflicts of interest are reported by the authors.

  • 37. Juras, Anna
    et al.
    Krzewińska, Maja
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies, Archaeological Research Laboratory.
    Nikitin, Alexey G.
    Ehler, Edvard
    Chylenski, Maciej
    Lukasik, Sylwia
    Krenz-Niedbala, Marta
    Sinika, Vitaly
    Piontek, Janusz
    Ivanova, Svetlana
    Dabert, Miroslawa
    Götherström, Anders
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies, Archaeological Research Laboratory.
    Diverse origin of mitochondrial lineages in Iron Age Black Sea Scythians2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 43950Article in journal (Refereed)
    Abstract [en]

    Scythians were nomadic and semi-nomadic people that ruled the Eurasian steppe during much of the first millennium BCE. While having been extensively studied by archaeology, very little is known about their genetic identity. To fill this gap, we analyzed ancient mitochondrial DNA (mtDNA) from Scythians of the North Pontic Region (NPR) and successfully retrieved 19 whole mtDNA genomes. We have identified three potential mtDNA lineage ancestries of the NPR Scythians tracing back to huntergatherer and nomadic populations of east and west Eurasia as well as the Neolithic farming expansion into Europe. One third of all mt lineages in our dataset belonged to subdivisions of mt haplogroup U5. A comparison of NPR Scythian mtDNA linages with other contemporaneous Scythian groups, the Saka and the Pazyryks, reveals a common mtDNA package comprised of haplogroups H/H5, U5a, A, D/D4, and F1/F2. Of these, west Eurasian lineages show a downward cline in the west-east direction while east Eurasian haplogroups display the opposite trajectory. An overall similarity in mtDNA lineages of the NPR Scythians was found with the late Bronze Age Srubnaya population of the Northern Black Sea region which supports the archaeological hypothesis suggesting Srubnaya people as ancestors of the NPR Scythians.

  • 38.
    Kegel, Andreas
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Silencing and DNA double-strand break repair in budding yeast2006Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Transcriptional silencing that makes large chromosomal domains inaccessible for the transcriptional apparatus is nucleated at DNA elements called silencers. In K.lactis a 102bp HMLα silencer was defined revealing three distinct protein-binding regions (A, B, and C) that were required for silencing of HMLα. The B-sequence was a binding-site for the transcription factor Reb1. Temperature sensitive reb1 alleles displayed silencing defects at the restrictive temperature. In addition, point mutations in the B-sequence abolished both Reb1-binding and silencer function. Silencing in the related yeast S.cerevisiae does not require Reb1 indicating that silencer-binding proteins diverge rapidly in hemiascomysetous species.

    Yeast strains lacking Sir2, Sir3 or Sir4 display a defect in the DNA double-strand break repair pathway, called nonhomologous end joining (NHEJ). We identified the first haploid-specific gene (NEJ1) involved in DSB repair and demonstrated that the NHEJ defect of sir mutants was largely attributable to the transcriptional repression of NEJ1. Cells lacking Nej1 initially slowed down the 5´to 3´DNA degradation rate at a DSB suggesting that Nej1 has a direct role in end joining repair. The localization of Nej1 to the nucleus and a direct molecular interaction with the NHEJ protein Lif1 supported this notion. Indirect participation of Nej1 in end joining by regulating the transport or stability of Lif1 was excluded.

    In K.lactis integration of exogenous DNA via illegitimate recombination (IR) occurred with a high frequency and was completely dependent on the NHEJ pathway. NHEJ was capable of efficient repair of a wide variety of DNA ends and both haploid and diploid cells performed NHEJ with the same efficiency. Furthermore, IR preferentially took place within intergenic regions and ribosomal DNA. A rad52 mutant had no affect on targeting preference for IGRs indicating that DSBs in ORFs were not primarily repaired by homologous recombination (HR). Introduction of an ectopic DSB preferentially targeted IR to this site. Thus, we suggest that IR occurs at DSBs and by analysing IR-events spontaneously arising mitotic DSBs can be mapped.

  • 39.
    Kodandaramaiah, Ullasa
    Stockholm University, Faculty of Science, Department of Zoology.
    Eyespot evolution: phylogenetic insights from Junonia and related butterfly genera (Nymphalidae)2009In: Evolution & Development, ISSN 1520-541X, E-ISSN 1525-142X, Vol. 11, no 5, p. 489-497Article in journal (Refereed)
    Abstract [en]

    Butterfly eyespots have been the focus of a number of developmental and evolutionary studies. However, a phylogenetic component has rarely been explicitly incorporated in these studies. In this study, I utilize a phylogeny to trace the evolution of eyespot number and position on the wing in a group of nymphalid butterflies, the subtribe Junoniini. These butterflies have two kinds of eyespot arrangements which I refer to as Serial and Individual. In the Serial arrangement, eyespots are placed in a series on compartments 1-6 (counting from the anterior wing margin). In the Individual arrangement, eyespots are isolated on specific compartments, ranging from 1 to 4 in number. This can be divided into four subtypes based on the number and positions of eyespots. I map the evolution of these five arrangements over a phylogeny of Junoniini reconstructed with ca. 3000 base pairs of sequence data from three genes. The results show that almost all arrangements have evolved at least twice, with multiple shifts between them by addition and deletion of eyespots. I propose a model involving genetic or developmental coupling between eyespots in specific compartments to explain these shifts. I discuss their evolution in light of existing knowledge about their development. I also discuss potential explanations for functional significance of the eyespot patterns found in the group. Differential selection for and against eyespots, both at different times over the phylogeny and in different regions, have driven the evolution of eyespot arrangements. The study throws open many questions about the adaptive significance of eyespots and the developmental underpinnings of the various arrangements.

  • 40.
    Kodandaramaiah, Ullasa
    Stockholm University, Faculty of Science, Department of Zoology, Animal Ecology.
    Vagility - the neglected component in historical biogeography2009In: Evolutionary biology, ISSN 0071-3260, E-ISSN 1934-2845, Vol. 36, no 3, p. 327-335Article in journal (Refereed)
    Abstract [en]

    The conceptual gap between ecological and historical biogeography is wide, although both disciplines are concerned with explaining how distributions have been shaped. A central aim of modern historical biogeography is to use a phylogenetic framework to reconstruct the geographic history of a group in terms of dispersals and vicariant events, and a number of analytical methods have been developed to do so. To date the most popular analytical methods in historical biogeography have been parsimony-based. Such methods can be classified into two groups based on the assumptions used. The first group assumes that vicariance between two areas creates common patterns of disjunct distributions across several taxa whereas dispersals and extinctions generate clade specific patterns. The second group of methods assumes that passive vicariance and within-area speciation have a higher probability of occurrence than active dispersal events and extinction. Typically, none of these methods takes into account the ecology of the taxa in question. I discuss why these methods can be potentially misleading if the ecology of the taxon is ignored. In particular, the vagility or dispersal ability of taxa plays a pivotal role in shaping the distributions and modes of speciation. I argue that the vagility of taxa should be explicitly incorporated in biogeographic analyses. Likelihood-based methods with models in which more realistic probabilities of dispersal and modes of speciation can be specified are arguably the way ahead. Although objective quantification will pose a challenge, the complete ignorance of this vital aspect, as has been done in many historical biogeographic analyses, can be dangerous. I use worked examples to show a simple way of utilizing such information, but better methods need to be developed to more effectively use ecological knowledge in historical biogeography.

  • 41. Krauss-Etschmann, Susanne
    et al.
    Bush, Andrew
    Bellusci, Saverio
    Brusselle, Guy G
    Erik K Dahlén, Sven
    Dehmel, Stefan
    Eickelberg, Oliver
    Gibson, Greg
    Hylkema, Machteld N
    Knaus, Petra
    Königshoff, Melanie
    Lloyd, Clare M
    Macciarini, Paolo
    Mailleux, Arnaud
    Marsland, Benjamin J
    Postma, Dirkje S
    Roberts, Graham
    Samakovlis, Christos
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Stocks, Janet
    Vandesompele, Joke
    Wjst, Matthias
    Holloway, John
    Of flies, mice and men: a systematic approach to understanding the early life origins of chronic lung disease2013In: Thorax, ISSN 0040-6376, E-ISSN 1468-3296, Vol. 68, no 4, p. 380-384Article in journal (Refereed)
    Abstract [en]

    Despite intensive research efforts, the aetiology of the majority of chronic lung diseases (CLD) in both, children and adults, remains elusive. Current therapeutic options are limited, providing only symptomatic relief, rather than treating the underlying condition, or preventing its development in the first place. Thus, there is a strong and unmet clinical need for the development of both, novel effective therapies and preventative strategies for CLD. Many studies suggest that modifications of prenatal and/or early postnatal lung development will have important implications for future lung function and risk of CLD throughout life. This view represents a fundamental change of current pathophysiological concepts and treatment paradigms, and holds the potential to develop novel preventative and/or therapeutic strategies. However, for the successful development of such approaches, key questions, such as a clear understanding of underlying mechanisms of impaired lung development, the identification and validation of relevant preclinical models to facilitate translational research, and the development of concepts for correction of aberrant development, all need to be solved. Accordingly, a European Science Foundation Exploratory Workshop was held where clinical, translational and basic research scientists from different disciplines met to discuss potential mechanisms of developmental origins of CLD, and to identify major knowledge gaps in order to delineate a roadmap for future integrative research.

  • 42.
    Krautz, Robert
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Khalili, Dilan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Söll, Iris
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hauptmann, Giselbert
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Drosophila larval fat body preparations to reveal regionalized gene expression​Manuscript (preprint) (Other academic)
  • 43.
    Kvarnemo, Charlotta
    et al.
    Göteborgs universitet.
    Lindenfors, Patrik
    Stockholm University, Faculty of Science, Department of Zoology, Animal Ecology. Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution.
    Ah-King, Malin
    Stockholm University, Faculty of Science, Department of Zoology, Animal Ecology.
    Ahnesjö, Ingrid
    Uppsala universitet.
    Workshop review of: Gender perspectives on the development of sexual selection theory, Uppsala, October 20082009In: ISBE Newsletter, Vol. 21, no 1, p. 11-13Article in journal (Other academic)
  • 44.
    Lagerholm, Vendela K.
    et al.
    Stockholm University, Faculty of Science, Department of Zoology. Swedish Museum of Natural History, Sweden.
    Sandoval-Castellanos, Edson
    Stockholm University, Faculty of Science, Department of Zoology. Swedish Museum of Natural History, Sweden.
    Ehrich, Dorothee
    Abramson, Natalia I.
    Nadachowski, Adam
    Kalthoff, Daniela C.
    Germonpre, Mietje
    Angerbjörn, Anders
    Stockholm University, Faculty of Science, Department of Zoology.
    Stewart, John R.
    Dalén, Love
    On the origin of the Norwegian lemming2014In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 23, no 8, p. 2060-2071Article in journal (Refereed)
    Abstract [en]

    The Pleistocene glacial cycles resulted in significant changes in species distributions, and it has been discussed whether this caused increased rates of population divergence and speciation. One species that is likely to have evolved during the Pleistocene is the Norwegian lemming (Lemmus lemmus). However, the origin of this species, both in terms of when and from what ancestral taxon it evolved, has been difficult to ascertain. Here, we use ancient DNA recovered from lemming remains from a series of Late Pleistocene and Holocene sites to explore the species' evolutionary history. The results revealed considerable genetic differentiation between glacial and contemporary samples. Moreover, the analyses provided strong support for a divergence time prior to the Last Glacial Maximum (LGM), therefore likely ruling out a postglacial colonization of Scandinavia. Consequently, it appears that the Norwegian lemming evolved from a small population that survived the LGM in an ice-free Scandinavian refugium.

  • 45.
    Leneveu, Julien
    et al.
    University of Turku, Finland.
    Chichvarkhin, Anton
    Inst Biol Soil Sci, Vladivostok, Russia.
    Wahlberg, Niklas
    Stockholm University, Faculty of Science, Department of Zoology.
    Varying rates of diversification in the genus Melitaea (Lepidoptera: Nymphalidae) during the past 20 million years2009In: Biological Journal of the Linnean Society, ISSN 0024-4066, E-ISSN 1095-8312, Vol. 97, no 2, p. 346-361Article in journal (Refereed)
    Abstract [en]

    The influence of Quarternary glacial cycles on the extant diversity of Holarctic species has been intensively studied. It has been hypothesized that palaeoclimatic changes are responsible for divergence events in lineages. A constant improvement in DNA sequencing and modeling methods, as well as palaeoclimatic reconstruction, permit a deeper exploration of general causes of speciation in geological time. In the present study, we sampled, as exhaustively as possible, the butterflies belonging to the genus Melitaea (Lepidoptera: Nymphalidae), which are widely spread in the Palaearctic region. We conducted analyses to assess the phylogeny of the genus and estimated the timing of divergence and the most likely distribution of ancestral populations. The results obtained indicate that the systematics of the genus is in need of revision and that the diversity of the genus has been profoundly shaped by palaeoenvironmental changes during its evolutionary history. The present study also emphasizes that, when employed with caveats, major palaeoenvironmental events could represent very powerful tools for the calibration of the dating of divergences using molecular data.

  • 46.
    Lilja, Tobias
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Functions of Transcriptional Co-regulators in Drosophila development2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    During Drosophila development, regulation of gene expression through interplay between transcriptional activators and repressors is generating complex patterns of gene expression that leads to cell differentiation. For proper control of transcription, transcription factors bind to DNA at control regions, so called Cis Regulatory Modules (CRM). Transcription factors recruit additional factors, co-regulators, that affect gene expression through interactions with the general transcription machinery, as well as affect the chromatin environment through post-translational modifications of the histone tails. In this thesis the role of transcriptional co-regulators in Drosophila development is investigated.

    This work has demonstrated the need for the transcriptional co-activator CREB binding protein (CBP) in signalling by the Transforming Growth Factor-β (TGF-β) molecules Decapentaplegic (Dpp) and Screw (Scw) in early embryos. Furthermore it is shown that the acetyl transferase activity of CBP is dispensable for this function.

    In a screen for novel regulators of gene expression in the embryo, Brakeless (Bks) was isolated as a co-repressor for the Tailless (Tll) transcription factor. This work shows that Tll function is impaired in bks mutants, that Bks and Tll bind each other in vitro and interact genetically. Bks is present on CRMs controlled by Tll and can repress transcription when tethered to DNA. Bks interacts and functions together with another co-repressor Atrophin.

    Reptin is part of several complexes including the TIP60 Histone Acetyl Transferase (HAT) complex. Work in this thesis show that Reptin and other members of the TIP60 complex function in formation of silent chromatin in Drosophila.

    Together these results show that transcriptional co-regulators function selectively in specific processes during development.

  • 47.
    Lilja, Tobias
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Aihara, Hitoshi
    Stabell, Marianne
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nibu, Yutaka
    Mannervik, Mattias
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    The acetyltransferase activity of Drosophila CBP is dispensable for regulation of the Dpp pathway in the early embryo2007In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 305, no 2, p. 650-658Article in journal (Refereed)
    Abstract [en]

    The CBP protein is a transcriptional co-activator and histone acetyltransferase. Reduced expression of Drosophila CBP (dCBP) in the early embryo specifically impairs signaling by the TGF-β molecules Dpp and Screw (Scw). This occurs by a failure to activate transcription of the tolloid (tld) gene, which codes for a protease that generates active Dpp and Scw ligands. We show that dCBP directly regulates this gene by binding to the tld enhancer, and that tld expression can be partially rescued with a dCBP transgene. At a slightly later stage of development, Dpp/Scw signaling recovers in mutant embryos, but is unable to turn on expression of the Dpp/Scw-target gene rhomboid (rho). Interestingly, an acetyltransferase (AT)-defective dCBP transgene rescued tld and rho gene expression to an extent comparable to the wild-type transgene, whereas a transgene containing a 130 amino acid deletion rescued tld but not late rho expression. A tracheal phenotype caused by the reduced dCBP levels was also rescued more efficiently with the wild-type dCBP transgene than with this mutant transgene. Our results indicate that separate parts of the dCBP protein are required on different promoters, and that the AT activity of dCBP is dispensable for certain aspects of Dpp signaling. We discuss the similarity of these results to the role of p300/CBP in TGF-β signaling in the mouse.

  • 48.
    Lind, Johan
    et al.
    Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution. Stockholm University, Faculty of Science, Department of Zoology.
    Lindenfors, Patrik
    Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution. Stockholm University, Faculty of Science, Department of Zoology.
    Ghirlanda, Stefano
    Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution. Brooklyn College, USA.
    Lidén, Kerstin
    Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution. Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies.
    Enquist, Magnus
    Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution. Stockholm University, Faculty of Science, Department of Zoology.
    Dating human cultural capacity using phylogenetic principles2013In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 3, article id 1785Article in journal (Refereed)
    Abstract [en]

    Humans have genetically based unique abilities making complex culture possible; an assemblage of traits which we term cultural capacity. The age of this capacity has for long been subject to controversy. We apply phylogenetic principles to date this capacity, integrating evidence from archaeology, genetics, paleoanthropology, and linguistics. We show that cultural capacity is older than the first split in the modern human lineage, and at least 170,000 years old, based on data on hyoid bone morphology, FOXP2 alleles, agreement between genetic and language trees, fire use, burials, and the early appearance of tools comparable to those of modern hunter-gatherers. We cannot exclude that Neanderthals had cultural capacity some 500,000 years ago. A capacity for complex culture, therefore, must have existed before complex culture itself. It may even originated long before. This seeming paradox is resolved by theoretical models suggesting that cultural evolution is exceedingly slow in its initial stages.

  • 49.
    Löfstrand, Stefan D.
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Faculty of Science, The Bergius Botanical Garden Museum. University of Vienna, Austria.
    Krüger, Åsa
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Faculty of Science, The Bergius Botanical Garden Museum.
    Razafimandimbison, Sylvain G.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Faculty of Science, The Bergius Botanical Garden Museum.
    Bremer, Birgitta
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Faculty of Science, The Bergius Botanical Garden Museum.
    Phylogeny and Generic Delimitations in the Sister Tribes Hymenodictyeae and Naucleeae (Rubiaceae)2014In: Systematic Botany, ISSN 0363-6445, E-ISSN 1548-2324, Vol. 39, no 1, p. 304-315Article in journal (Refereed)
    Abstract [en]

    The Hymenodicteae-Naudeeae clade is a predominantly Paleotropical group with 220 species in 28 genera. The phylogertetic relationships and generic limits within Naucleeae have previously been assessed using combined molecular-morphological data, however the status of some genera remains questionable. The evolutionary relationships within Hymenodictyeae have never been investigated before. We performed phylogenetic analyses of the Hymenodictyeae-Naucleeae clade using nuclear [nrETS; nrITS] and chloroplast [ndhF; rbcL; rps16; trnT-F] data and a large sampling of both tribes. Our study supports the monophyly of the tribes, all subtribes of Naucleeae (Adininae, Breoniinae, Cephalanthinae, Corynantheinae, Mitragyninae, Naucleinae, and Uncariinae), and the Hymenodictyeae genera Hymenodictyon and Paracorynanthe. In Naucleeae, the monotypic genera Adinauclea, Metadina, and Pertusadina are nested within Adina, Mitragyna within Fleroya, Ludekia, Myrmeconauclea, and Ochreinauclea within Neonauclea, and Burttdavya and Sarcocephalus within Nauclea. Corynanthe and Pausinystalia are mutually paraphyletic. We provisionally maintain the current generic status of Neonauclea and its allied genera, pending further study. In sum, we recognize 17 genera in Naucleeae: Adina s. l., Breonadia, Breonia, Cephalanthus, Corynanthe s. l., Diyaminauclea, Gyrostipula, Janotia, Khasiaclunea, Ludekia, Mitragyna s. l., Myrmeconauclea, Nauclea s. l., Neolamarckia, Neonauclea, Ochreinauclea, and Uncaria. Five new combinations were made: Adina euryncha, Adina malaccensis, Corynanthe lane-poolei subsp. iturense, Corynanthe talbotii, and Nauclea nyasica.

  • 50.
    Matsuda, Ryo
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Revisiting cell specification and differentiation in the Drosophila airways, an insect organ homologous to our lung and blood vessels2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Oxygen is essential for life. Aquatic ancestral animal species are thought to have independently terrestrialized and invented distinct strategies for efficient oxygen supply. The respiratory system of vertebrates like us is composed of lungs connected to the vasculature while insects have a single system delivering air directly to internal tissues. In spite of their different evolutionary histories, the formation of these different tubular networks is thought to share many cellular, genetic and molecular principles. Here, in register with preceding studies, I briefly introduce the projects of my co-authors and me, addressing several new aspects of specification and differentiation of the Drosophila airways.

    The airway primordia are specified at the lateral ectoderm of each side of the embryo as 10 groups of epithelial cells. These cells coordinately invaginate from the 2-dimensional (2D) ectodermal sheet to form 3D primitive tubes. The most proximal cells to the epidermis take the pluripotent cell fate and later generate most of the pupal and adult airways. Distal cells ramify to establish the primary branches and some neighboring branches fuse, interconnecting the network. Establishing these basic architectures, the tubular network matures into functional airways, attaining proper tube sizes in diameter and length, producing an annular-ridged lining of exoskeleton to avoid tube collapse and finally filling the system with gas.

    First, I present airway-promoting functions of factors that were previously assigned to repress the airway fate. Then, I present genetic frameworks discriminating between 3 ground cell fates and the more derived cell fates: A) the proximal pluripotent cells vs. the distal more differentiated cells, B) the visceral branch vs. the signal-induced primary branches and C) the 1st metamere vs. the more posterior metameres. Lastly, I present our efforts to identify genes converting the airway tubes into a functional respiratory system.

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