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  • 1.
    Aguilo, Francesca
    et al.
    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Zakirova, Zuchra
    Nolan, Katie
    Wagner, Ryan
    Sharma, Rajal
    Hogan, Megan
    Wei, Chengguo
    Sun, Yifei
    Walsh, Martin J.
    Kelley, Kevin
    Zhang, Weijia
    Ozelius, Laurie J.
    Gonzalez-Alegre, Pedro
    Zwaka, Thomas P.
    Ehrlich, Michelle E.
    THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation2017In: Stem Cell Reports, ISSN 2213-6711, Vol. 9, no 1, p. 92-107Article in journal (Refereed)
    Abstract [en]

    THAP1 (THAP [Thanatos-associated protein] domain-containing, apoptosis-associated protein 1) is a ubiquitously expressed member of a family of transcription factors with highly conserved DNA-binding and protein-interacting regions. Mutations in THAP1 cause dystonia, DYT6, a neurologic movement disorder. THAP1 downstream targets and the mechanism via which it causes dystonia are largely unknown. Here, we show that wild-type THAP1 regulates embryonic stem cell (ESC) potential, survival, and proliferation. Our findings identify THAP1 as an essential factor underlying mouse ESC survival and to some extent, differentiation, particularly neuroectodermal. Loss of THAP1 or replacement with a disease-causing mutation results in an enhanced rate of cell death, prolongs Nanog, Prdm14, and/or Rex1 expression upon differentiation, and results in failure to upregulate ectodermal genes. ChIP-Seq reveals that these activities are likely due in part to indirect regulation of gene expression.

  • 2.
    Alkhori, Liza
    et al.
    Linköpings universitet, Avdelningen för cellbiologi.
    Öst, Anita
    Linköpings universitet, Avdelningen för cellbiologi.
    Alenius, Mattias
    Linköpings universitet, Avdelningen för cellbiologi.
    The corepressor Atrophin specifies odorant receptor expression in Drosophila2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 3, p. 1355-1364Article in journal (Refereed)
    Abstract [en]

    In both insects and vertebrates, each olfactory sensory neuron (OSN) expresses one odorant receptor (OR) from a large genomic repertoire. How a receptor is specified is a tantalizing question addressing fundamental aspects of cell differentiation. Here, we demonstrate that the corepressor Atrophin (Atro) segregates OR gene expression between OSN classes in Drosophila. We show that the knockdown of Atro result in either loss or gain of a broad set of ORs. Each OR phenotypic group correlated with one of two opposing Notch fates, Notch responding, Nba (N(on)), and nonresponding, Nab (N(off)) OSNs. Our data show that Atro segregates ORs expressed in the Nba OSN classes and helps establish the Nab fate during OSN development. Consistent with a role in recruiting histone deacetylates, immunohistochemistry revealed that Atro regulates global histone 3 acetylation (H3ac) in OSNs and requires Hdac3 to segregate OR gene expression. We further found that Nba OSN classes exhibit variable but higher H3ac levels than the Nab OSNs. Together, these data suggest that Atro determines the level of H3ac, which ensures correct OR gene expression within the Nba OSNs. We propose a mechanism by which a single corepressor can specify a large number of neuron classes.-Alkhori, L., Öst, A., Alenius, M. The corepressor Atrophin specifies odorant receptor expression in Drosophila.

  • 3. Andreae, Laura C
    et al.
    Peukert, Daniela
    Lumsden, Andrew
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Analysis of Lrrn1 expression and its relationship to neuromeric boundaries during chick neural development2007In: Neural Development, ISSN 1749-8104, Vol. 2, no 22, p. 1-16Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The Drosophila leucine-rich repeat proteins Tartan (TRN) and Capricious (CAPS) mediate cell affinity differences during compartition of the wing imaginal disc. This study aims to identify and characterize the expression of a chick orthologue of TRN/CAPS and examine its potential function in relation to compartment boundaries in the vertebrate central nervous system.

    RESULTS: We identified a complementary DNA clone encoding Leucine-rich repeat neuronal 1 (Lrrn1), a single-pass transmembrane protein with 12 extracellular leucine-rich repeats most closely related to TRN/CAPS. Lrrn1 is dynamically expressed during chick development, being initially localized to the neural plate and tube, where it is restricted to the ventricular layer. It becomes downregulated in boundaries following their formation. In the mid-diencephalon, Lrrn1 expression prefigures the position of the anterior boundary of the zona limitans intrathalamica (ZLI). It becomes progressively downregulated from the presumptive ZLI just before the onset of expression of the signalling molecule Sonic hedgehog (Shh) within the ZLI. In the hindbrain, downregulation at rhombomere boundaries correlates with the emergence of specialized boundary cell populations, in which it is subsequently reactivated. Immunocolocalization studies confirm that Lrrn1 protein is endocytosed from the plasma membrane and is a component of the endosomal system, being concentrated within the early endosomal compartment.

    CONCLUSION: Chick Lrrn1 is expressed in ventricular layer neuroepithelial cells and is downregulated at boundary regions, where neurogenesis is known to be delayed, or inhibited. The timing of Lrrn1 downregulation correlates closely with the activation of signaling molecule expression at these boundaries. This expression is consistent with the emergence of secondary organizer properties at boundaries and its endosomal localisation suggests that Lrrn1 may regulate the subcellular localisation of specific components of signalling or cell-cell recognition pathways in neuroepithelial cells.

  • 4.
    Berghard, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hägglund, Anna-Carin
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 8, p. 3464-3472Article in journal (Refereed)
    Abstract [en]

    Inactivation of the LIM-homeodomain 2 gene (Lhx2) results in a severe defect in specification of olfactory sensory neurons (OSNs). However, the ramifications of lack of Lhx2-dependent OSN specification for formation of the primary olfactory pathway have not been addressed, since mutant mice die in utero. We have analyzed prenatal and postnatal consequences of conditionally inactivating Lhx2 selectively in OSNs. A cell-autonomous effect is that OSN axons cannot innervate their target, the olfactory bulb. Moreover, the lack of Lhx2 in OSNs causes unpredicted, non-cell-autonomous phenotypes. First, the olfactory bulb shows pronounced hypoplasia in adults, and the data suggest that innervation by correctly specified OSNs is necessary for adult bulb size and organization. Second, absence of an olfactory nerve in the conditional mutant reveals that the vomeronasal nerve is dependent on olfactory nerve formation. Third, the lack of a proper vomeronasal nerve prevents migration of gonadotropin-releasing hormone (GnRH) cells the whole distance to their final positions in the hypothalamus during embryo development. As adults, the conditional mutants do not pass puberty, and these findings support the view of an exclusive nasal origin of GnRH neurons in the mouse. Thus, Lhx2 in OSNs is required for functional development of three separate systems.—Berghard, A., Hägglund, A.-C., Bohm, S., and Carlsson, L. Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons.

  • 5. Bhalerao, Rishikesh P
    et al.
    Eklöf, Jan
    Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, The Swedish University of Agricultural Sciences, SE-901 83, Umeå, Sweden.
    Ljung, Karin
    Marchant, Alan
    Bennett, Malcolm
    Sandberg, Göran
    Shoot-derived auxin is essential for early lateral root emergence in Arabidopsis seedlings2002In: The Plant Journal, ISSN 0960-7412, E-ISSN 1365-313X, Vol. 29, no 3, p. 325-332Article in journal (Refereed)
    Abstract [en]

    Lateral root formation is profoundly affected by auxins. Here we present data which indicate that light influences the formation of indole-3-acetic acid (IAA) in germinating Arabidopsis seedlings. IAA transported from the developing leaves to the root system is detectable as a short-lived pulse in the roots and is required for the emergence of the lateral root primordia (LRP) during early seedling development. LRP emergence is inhibited by the removal of apical tissues prior to detection of the IAA pulse in the root, but this treatment has minimal effects on LRP initiation. Our results identify the first developing true leaves as the most likely source for the IAA required for the first emergence of the LRP, as removal of cotyledons has only a minor effect on LRP emergence in contrast to removal of the leaves. A basipetal IAA concentration gradient with high levels of IAA in the root tip appears to control LRP initiation, in contrast to their emergence. A significant increase in the ability of the root system to synthesize IAA is observed 10 days after germination, and this in turn is reflected in the reduced dependence of the lateral root emergence on aerial tissue-derived auxin at this stage. We propose a model for lateral root formation during early seedling development that can be divided into two phases: (i) an LRP initiation phase dependent on a root tip-localized IAA source, and (ii) an LRP emergence phase dependent on leaf-derived IAA up to 10 days after germination.

  • 6.
    Boija, Ann
    et al.
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.
    Holmqvist, Per-Henrik
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå, Sweden.
    Zare, Aman
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå, Sweden.
    Meyers, David J.
    Dept. Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
    Cole, Philip A.
    Dept. Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Division of CBRN Defence and Security, FOI, Swedish Defence Research Agency, Sweden.
    Mannervik, Mattias
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, SwedenDept. Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
    Drosophila CBP cooperates with GAGA factor to induce high levels of Pol II promoter-proximal pausingManuscript (preprint) (Other academic)
  • 7. Bonn, Stefan
    et al.
    Zinzen, Robert P
    Girardot, Charles
    Gustafson, E Hilary
    Perez-Gonzalez, Alexis
    Delhomme, Nicolas
    Ghavi-Helm, Yad
    Wilczyński, Bartek
    Riddell, Andrew
    Furlong, Eileen E M
    Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development.2012In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, no 2Article in journal (Refereed)
    Abstract [en]

    Chromatin modifications are associated with many aspects of gene expression, yet their role in cellular transitions during development remains elusive. Here, we use a new approach to obtain cell type-specific information on chromatin state and RNA polymerase II (Pol II) occupancy within the multicellular Drosophila melanogaster embryo. We directly assessed the relationship between chromatin modifications and the spatio-temporal activity of enhancers. Rather than having a unique chromatin state, active developmental enhancers show heterogeneous histone modifications and Pol II occupancy. Despite this complexity, combined chromatin signatures and Pol II presence are sufficient to predict enhancer activity de novo. Pol II recruitment is highly predictive of the timing of enhancer activity and seems dependent on the timing and location of transcription factor binding. Chromatin modifications typically demarcate large regulatory regions encompassing multiple enhancers, whereas local changes in nucleosome positioning and Pol II occupancy delineate single active enhancers. This cell type-specific view identifies dynamic enhancer usage, an essential step in deciphering developmental networks.

  • 8. Brend, Tim
    et al.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Summerbell, Dennis
    Rigby, Peter W J
    Multiple levels of transcriptional and post-transcriptional regulation are required to define the domain of Hoxb4 expression2003In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 130, no 12, p. 2717-2728Article in journal (Refereed)
    Abstract [en]

    Hox genes are key determinants of anteroposterior patterning of animal embryos, and spatially restricted expression of these genes is crucial to this function. In this study, we demonstrate that expression of Hoxb4 in the paraxial mesoderm of the mouse embryo is transcriptionally regulated in several distinct phases, and that multiple regulatory elements interact to maintain the complete expression domain throughout embryonic development. An enhancer located within the intron of the gene (region C) is sufficient for appropriate temporal activation of expression and the establishment of the correct anterior boundary in the paraxial mesoderm (somite 6/7). However, the Hoxb4 promoter is required to maintain this expression beyond 8.5 dpc. In addition, sequences within the 3' untranslated region (region B) are necessary specifically to maintain expression in somite 7 from 9.0 dpc onwards. Neither the promoter nor region B can direct somitic expression independently, indicating that the interaction of regulatory elements is crucial for the maintenance of the paraxial mesoderm domain of Hoxb4 expression. We further report that the domain of Hoxb4 expression is restricted by regulating transcript stability in the paraxial mesoderm and by selective translation and/or degradation of protein in the neural tube. Moreover, the absence of Hoxb4 3'-untranslated sequences from transgene transcripts leads to inappropriate expression of some Hoxb4 transgenes in posterior somites, indicating that there are sequences within region B that are important for both transcriptional and post-transcriptional regulation.

  • 9. Broom, Emma R
    et al.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Butts, Thomas
    Campo-Paysaa, Florent
    Wingate, Richard J T
    The roof plate boundary is a bi-directional organiser of dorsal neural tube and choroid plexus development.2012In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 139, no 22, p. 4261-4270Article in journal (Refereed)
    Abstract [en]

    The roof plate is a signalling centre positioned at the dorsal midline of the central nervous system and generates dorsalising morphogenic signals along the length of the neuraxis. Within cranial ventricles, the roof plate gives rise to choroid plexus, which regulates the internal environment of the developing and adult brain and spinal cord via the secretion of cerebrospinal fluid. Using the fourth ventricle as our model, we show that the organiser properties of the roof plate are determined by its boundaries with the adjacent neuroepithelium. Through a combination of in ovo transplantation, co-culture and electroporation techniques in chick embryos between embryonic days 3 and 6, we demonstrate that organiser properties are maintained by interactions between the non-neural roof plate and the neural rhombic lip. At the molecular level, this interaction is mediated by Delta-Notch signalling and upregulation of the chick homologue of Hes1: chairy2. Gain- and loss-of-function approaches reveal that cdelta1 is both necessary and sufficient for organiser function. Our results also demonstrate that while chairy2 is specifically required for the maintenance of the organiser, its ectopic expression is not sufficient to recapitulate organiser properties. Expression of atonal1 in the rhombic lip adjacent at the roof plate boundary is acutely dependent on both boundary cell interactions and Delta-Notch signalling. Correspondingly, the roof plate boundary organiser also signals to the roof plate itself to specify the expression of early choroid plexus markers. Thus, the roof plate boundary organiser signals bi-directionally to acutely coordinate the development of adjacent neural and non-neural tissues.

  • 10.
    Burguière, Anne-Cecile
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Hanna
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    von Hofsten, Jonas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Alkali-like myosin light chain-1 (myl1) is an early marker for differentiating fast muscle cells in zebrafish2011In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 240, no 7, p. 1856-1863Article in journal (Refereed)
    Abstract [en]

    During myogenesis, muscle precursors become divided into either fast- or slow-twitch fibres, which in the zebrafish occupy distinct domains in the embryo. Genes encoding sarcomeric proteins specific for fast or slow fibres are frequently used as lineage markers. In an attempt to identify and evaluate early definitive markers for cells in the fast-twitch pathway, we analysed genes encoding proteins contributing to the fast sarcomeric structures. The previously uncharacterized zebrafish alkali-like myosin light chain gene (myl1) was found to be expressed exclusively in cells in the fast-twitch pathway initiated at an early stage of fast fibre differentiation. Myl1 was expressed earlier, and in a more fibre type restricted manner, than any of the previously described and frequently used fast myosin light and heavy chain and troponin muscle markers mylz2, mylz3, tnni2, tnnt3a, fMyHC1.3. In summary, this study introduces a novel marker for early differentiating fast muscle cells.

  • 11. Caballero-Pérez, Juan
    et al.
    Espinal-Centeno, Annie
    Falcon, Francisco
    García-Ortega, Luis F.
    Curiel-Quesada, Everardo
    Cruz-Hernández, Andrés
    Bako, Laszlo
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Chen, Xuemei
    Martínez, Octavio
    Alberto Arteaga-Vázquez, Mario
    Herrera-Estrella, Luis
    Cruz-Ramírez, Alfredo
    Transcriptional landscapes of Axolotl (Ambystoma mexicanum)2018In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 433, no 2, p. 227-239Article in journal (Refereed)
    Abstract [en]

    The axolotl (Ambystoma mexicanum) is the vertebrate model system with the highest regeneration capacity. Experimental tools established over the past 100 years have been fundamental to start unraveling the cellular and molecular basis of tissue and limb regeneration. In the absence of a reference genome for the Axolotl, transcriptomic analysis become fundamental to understand the genetic basis of regeneration.

    Here we present one of the most diverse transcriptomic data sets for Axolotl by profiling coding and non coding RNAs from diverse tissues. We reconstructed a population of 115,906 putative protein coding mRNAs as full ORFs (including isoforms). We also identified 352 conserved miRNAs and 297 novel putative mature miRNAs.

    Systematic enrichment analysis of gene expression allowed us to identify tissue-specific protein-coding transcripts. We also found putative novel and conserved microRNAs which potentially target mRNAs which are reported as important disease candidates in heart and liver.

  • 12.
    Chen, Sa
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Anna L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Tegeling, Erik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Rasmuson Lestander, Asa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    In vivo analysis of Suppressor of zeste 12´s different isoformsManuscript (Other academic)
    Abstract [en]

    Polycomb Group (PcG) genes are known to encode a large chromatin-associated family of proteins which are involved in genomic regulation of many cellular processes. Su(z)12 is a key component in PcG silencing. It is needed for three levels of methylation of histone 3 lysine 27 in vivo in Drosophila. Here, we report that Su(z)12 may exist in different isoforms and that these isoforms are spatially and temporally regulated. The biological function of the Su(z)12-A and -B isoforms seems to be very different. For instance the transgenic Su(z)12-B and the human homolog SUZ12, but not Su(z)12-A, rescue Su(z)12 mutants. Furthermore, transgenic flies over-expressing Su(z)12-B show typical homeotic transformation phenotypes, while over-expression of Su(z)12-A does not. However, the two isoforms appears to be able to substitute for each other in some aspects. During larval and pupal stages, Su(z)12-A seems to play the main role. 

  • 13.
    Chen, Sa
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rasmuson-Lestander, Åsa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Regulation of the Drosophila engrailed gene by Polycomb repressor complex 22009In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 126, no 5-6, p. 443-448Article in journal (Refereed)
    Abstract [en]

    Suppressor-of-zeste-12 (Su(z)12) is a core component of the Polycomb repressive complex 2 (PRC2), which has a methyltransferase activity directed towards lysine residues of histone 3. Mutations in Polycomb group (PcG) genes cause de-repression of homeotic genes and subsequent homeotic transformations. Another target for Polycomb silencing is the engrailed gene, which encodes a key regulator of segmentation in the early Drosophila embryo. In close proximity to the en gene is a Polycomb Response Element, but whether en is regulated by Su(z)12 is not known. In this report, we show that en is not de-repressed in Su(z)12 or Enhancer-of-zeste mutant clones in the anterior compartment of wing discs. Instead, we find that en expression is down-regulated in the posterior portion of wing discs, indicating that the PRC2 complex acts as an activator of en. Our results indicate that this is due to secondary effects, probably caused by ectopic expression of Ubx and Abd-B.

  • 14. Coutinho, Ana P
    et al.
    Borday, Caroline
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jungbluth, Stefan
    Champagnat, Jean
    Lumsden, Andrew
    Fortin, Gilles
    Induction of a parafacial rhythm generator by rhombomere 3 in the chick embryo.2004In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 24, no 42, p. 9383-9390Article in journal (Refereed)
    Abstract [en]

    Observations of knock-out mice suggest that breathing at birth requires correct development of a specific hindbrain territory corresponding to rhombomeres (r) 3 and 4. Focusing on this territory, we examined the development of a neuronal rhythm generator in the chick embryo. We show that rhythmic activity in r4 is inducible after developmental stage 10 through interaction with r3. Although the nature of this interaction remains obscure, we find that the expression of Krox20, a segmentation gene responsible for specifying r3 and r5, is sufficient to endow other rhombomeres with the capacity to induce rhythmic activity in r4. Induction is robust, because it can be reproduced with r2 and r6 instead of r4 and with any hindbrain territory that normally expresses Krox20 (r3, r5) or can be forced to do so (r1, r4). Interestingly, the interaction between r4 and r3/r5 that results in rhythm production can only take place through the anterior border of r4, revealing a heretofore unsuspected polarity in individual rhombomeres. The r4 rhythm generator appears to be homologous to a murine respiratory parafacial neuronal system developing in r4 under the control of Krox20 and Hoxa1. These results identify a late role for Krox20 at the onset of neurogenesis.

  • 15.
    Davoine, Celine
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Abreu, Ilka N.
    Khajeh, Khalil
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Blomberg, Jeanette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kidd, Brendan N.
    Kazan, Kemal
    Schenk, Peer M.
    Gerber, Lorenz
    Nilsson, Ove
    Moritz, Thomas
    Björklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Functional metabolomics as a tool to analyze Mediator function and structure in plants2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0179640Article in journal (Refereed)
    Abstract [en]

    Mediator is a multiprotein transcriptional co-regulator complex composed of four modules; Head, Middle, Tail, and Kinase. It conveys signals from promoter-bound transcriptional regulators to RNA polymerase II and thus plays an essential role in eukaryotic gene regulation. We describe subunit localization and activities of Mediator in Arabidopsis through metabolome and transcriptome analyses from a set of Mediator mutants. Functional metabolomic analysis based on the metabolite profiles of Mediator mutants using multivariate statistical analysis and heat-map visualization shows that different subunit mutants display distinct metabolite profiles, which cluster according to the reported localization of the corresponding subunits in yeast. Based on these results, we suggest localization of previously unassigned plant Mediator subunits to specific modules. We also describe novel roles for individual subunits in development, and demonstrate changes in gene expression patterns and specific metabolite levels in med18 and med25, which can explain their phenotypes. We find that med18 displays levels of phytoalexins normally found in wild type plants only after exposure to pathogens. Our results indicate that different Mediator subunits are involved in specific signaling pathways that control developmental processes and tolerance to pathogen infections.

  • 16.
    Dorafshan Esfahani, Eshagh
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University.
    Methyltransferase Ash1, histone methylation and their impact on Polycomb repression2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Antagonistic interactions between Polycomb Group (PcG) and Trithorax Group (TrxG) proteins orchestrate the expression of key developmental genes. Distinct maternally loaded repressors establish the silenced state of these genes in cells where they should not be expressed and later PcG proteins sense whether a target gene is inactive and maintain the repression throughout multiple cell divisions. PcG proteins are targeted to genes by DNA elements called Polycomb Response Elements (PREs). The proteins form two major classes of complexes, namely Polycomb Repressive Complex 1 (PRC1) and Polycomb Repressive Complex 2 (PRC2). Mechanistic details of Polycomb repression are not fully understood, however, tri-methylation of Lysine 27 of histone H3 (H3K27me3) is essential for this process. Using Drosophila cell lines deficient for either PRC1 or PRC2, I investigated the role of H3K27 methylation and the interdependence of PRC1 complexes for their recruitment to PREs. My results indicate that recruitment of PcG complexes to PREs proceed via multiple pathways and that H3K27 methylation is not needed for their targeting. However, the methylation is required to stabilize interactions of PRE-anchored PcG complexes with surrounding chromatin.

    TrxG proteins prevent erroneous repression of Polycomb target genes where these genes need to be expressed. Ash1 is a TrxG protein which binds Polycomb target genes when they are transcriptionally active. It contains a SET domain which methylates Lysine 36 of histone H3 (H3K36). In vitro, histone H3 methylated at K36 is a poor substrate for H3K27 methylation by PRC2. This prompted a model where Ash1 counteracts Polycomb repression through H3K36 methylation. However, this model was never tested in vivo and does not consider several experimental observations. First, in the ash1 mutant flies the bulk H3K36me2/H3K36me3 levels remain unchanged. Second, in Drosophila, there are two other H3K36-specific histone methyltransferases, NSD and Set2, which should be capable to inhibit PRC2. Third, Ash1 contains multiple evolutionary conserved domains whose roles have not been investigated. Therefore, I asked whether H3K36 methylation is critical for Ash1 to counteract Polycomb repression in vivo and whether NSD and Set2 proteins contribute to this process. I used flies lacking endogenous histone genes and complemented them with transgenic histone genes where Lysine 36 is replaced by Arginine. In these animals, I assayed erroneous repression of HOX genes as a readout for erroneous Polycomb repression. I used the same readout in the NSD or Set2 mutant flies. I also asked if other conserved domains of Ash1 are essential for its function. In addition to SET and domain, Ash1 contains three AT hook motifs as well as BAH and PHD domains. I genetically complemented ash1 loss of function animals with transgenic Ash1 variants, in each, one domain of Ash1 is deleted. I found that Ash1 is the only H3K36-specific histone methyltransferase which counteracts Polycomb repression in Drosophila. My findings suggest that the model, where Ash1 counteracts PcG repression by inhibiting PRC2 via methylation of H3K36, has to be revised. I also showed that, in vivo, Ash1 acts as a multimer and requires SET, BAH and PHD domains to counteract Polycomb repression.

    This work led to two main conclusions. First, trimethylation of H3K27 is not essential for targeting PcG proteins to PREs but acts afterwards to stabilize their interaction with the chromatin of the neighboring genes. Second, while SET domain is essential for Ash1 to oppose Polycomb repression, methylation of H3K36 does not play a central role in the process.

    The full text will be freely available from 2019-12-18 00:01
  • 17.
    Dorafshan, Eshagh
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kahn, Tatyana G.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Glotov, Alexander
    Savitsky, Mikhail
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Walther, Matthias
    Reuter, Gunter
    Schwartz, Yuri B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Does Ash1 counteract Polycomb repression by methylating H3K36?Manuscript (preprint) (Other academic)
    Abstract [en]

    Polycomb repression is critical to maintain cell type specific genome expression programs in a wide range of multicellular animals. Equally important but less studied is the Trithorax group system, which safeguards Polycomb target genes from the repression in cells where they have to remain active. Based on in vitro studies it was proposed that the Trithorax group system acts via methylation of histone H3 at Lysine 4 (H3K4) and Lysine 36 (H3K36) thereby inhibiting histone methyltransferase activity of the Polycomb complexes. This hypothesis is yet to be comprehensively tested in vivo. Here we used the power of the Drosophila model to investigate how the Trithorax group protein Ash1 and the H3K36 methylation counteract Polycomb repression. We show, for the first time, that Ash1 is the only Drosophila H3K36-specific methyltransferase required to prevent excessive Polycomb repression of homeotic genes. Unexpectedly, our experiments revealed no correlation between the extent of H3K36 methylation and the resistance to Polycomb repression. Furthermore, we find that complete substitution of the zygotic histone H3 with a variant in which Lysine 36 is replaced by Arginine does not cause excessive repression of Drosophila homeotic genes. Together with earlier studies, our results suggest that the model, where the Trithorax group proteins methylate histone H3 to inhibit the histone methyltransferase activity of the Polycomb complexes, may need to be reevaluated.

  • 18.
    Dorafshan, Eshagh
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kahn, Tatyana G.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Schwartz, Yuri B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hierarchical recruitment of Polycomb complexes revisited2017In: Nucleus, ISSN 1949-1034, E-ISSN 1949-1042, Vol. 8, no 5, p. 496-505Article in journal (Refereed)
    Abstract [en]

    Polycomb Group (PcG) proteins epigenetically repress key developmental genes and thereby control alternative cell fates. PcG proteins act as complexes that can modify histones and these histone modifications play a role in transmitting the memory of the repressed state as cells divide. Here we consider mainstream models that link histone modifications to hierarchical recruitment of PcG complexes and compare them to results of a direct test of interdependence between PcG complexes for recruitment to Drosophila genes. The direct test indicates that PcG complexes do not rely on histone modifications to recognize their target genes but use them to stabilize the interactions within large chromatin domains. It also shows that multiple strategies are used to coordinate the targeting of PcG complexes to different genes, which may make the repression of these genes more or less robust.

  • 19.
    Dubreuil, Carole
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Ji, Yan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Strand, Åsa
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Grönlund, Andreas
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    A quantitative model of the phytochrome-PIF light signalling initiating chloroplast development2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 13884Article in journal (Refereed)
    Abstract [en]

    The components required for photosynthesis are encoded in two separate genomes, the nuclear and the plastid. To address how synchronization of the two genomes involved can be attained in early light-signalling during chloroplast development we have formulated and experimentally tested a mathematical model simulating light sensing and the following signalling response. The model includes phytochrome B (PhyB), the phytochrome interacting factor 3 (PIF3) and putative regulatory targets of PIF3. Closed expressions of the phyB and PIF3 concentrations after light exposure are derived, which capture the relevant timescales in the response of genes regulated by PIF3. Sequence analysis demonstrated that the promoters of the nuclear genes encoding sigma factors (SIGs) and polymerase-associated proteins (PAPs) required for expression of plastid encoded genes, contain the cis-elements for binding of PIF3. The model suggests a direct link between light inputs via PhyB-PIF3 to the plastid transcription machinery and control over the expression of photosynthesis components both in the nucleus and in the plastids. Using a pluripotent Arabidopsis cell culture in which chloroplasts develop from undifferentiated proplastids following exposure to light, we could experimentally verify that the expression of SIGs and PAPs in response to light follow the calculated expression of a PhyB-PIF3 regulated gene.

  • 20.
    Dubreuil, Carole
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå 901 83, Sweden.
    Jin, Xu
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå 901 83, Sweden.
    Grönlund, Andreas
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Fischer, Urs
    A local auxin gradient regulates root cap self-renewal and size homeostasis2018In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 28, no 16, p. 2581-+Article in journal (Refereed)
    Abstract [en]

    Organ size homeostasis, compensatory growth to replace lost tissue, requires constant measurement of size and adjustment of growth rates. Morphogen gradients control organ and tissue sizes by regulating stem cell activity, cell differentiation, and removal in animals [1-3]. In plants, control of tissue size is of specific importance in root caps to protect the growing root tip from mechanical damage [4]. New root cap tissue is formed by the columella and lateral root-cap-epidermal stem cells, whose activity is regulated through non-dividing niche-like cells, the quiescent center (QC) [4, 5]. Columella daughter cells in contact with the QC retain the potency to divide, while derivatives oriented toward the mature cap undergo differentiation. The outermost columella layers are sequentially separated from the root body, involving remodeling of cell walls [6]. Factors regulating the balance between cell division, elongation, and separation to keep root cap size constant are currently unknown [4]. Here, we report that stem cell proliferation induced cell separation at the periphery of the root cap, resulting in tissue size homeostasis. An auxin response gradient with a maximum in the QC and a minimum in the detaching layer was established prior to the onset of cell separation. In agreement with a mathematical model, tissue size was positively regulated by the amount of auxin released from the source. Auxin transporters localized non-polarly to plasma membranes of the inner cap, partly isolating separating layers from the auxin source. Together, these results are in support of an auxin gradient measuring and regulating tissue size.

  • 21.
    Eklöf, Jan
    Institutionen för skoglig genetik och växtfysiologi, Sveriges lantbruksuniversitet, 901 83 Umeå.
    Control of lateral root development in Arabidopsis thaliana2001Licentiate thesis, comprehensive summary (Other academic)
  • 22.
    Gilthorpe, Jonathan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Papantoniou, Elli-Kalliopi
    Chédotal, Alain
    Lumsden, Andrew
    Wingate, Richard J T
    The migration of cerebellar rhombic lip derivatives.2002In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 129, no 20, p. 4719-4728Article in journal (Refereed)
    Abstract [en]

    We have used cell labelling, co-culture and time-lapse confocal microscopy to investigate tangential neuronal migration from the rhombic lip. Cerebellar rhombic lip derivatives demonstrate a temporal organisation with respect to their morphology and response to migration cues. Early born cells, which migrate into ventral rhombomere 1, have a single long leading process that turns at the midline and becomes an axon. Later born granule cell precursors also migrate ventrally but halt at the lateral edge of the cerebellum, correlating with a loss of sensitivity to netrin 1 and expression of Robo2. The rhombic lip and ventral midline express Slit2 and both early and late migrants are repelled by sources of Slit2 in co-culture. These studies reveal an intimate relationship between birthdate, response to migration cues and neuronal fate in an identified population of migratory cells. The use of axons in navigating cell movement suggests that tangential migration is an elaboration of the normal process of axon extension.

  • 23.
    Gilthorpe, Jonathan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vandromme, Marie
    Brend, Tim
    Gutman, Alejandro
    Summerbell, Dennis
    Totty, Nick
    Rigby, Peter W J
    Spatially specific expression of Hoxb4 is dependent on the ubiquitous transcription factor NFY.2002In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 129, no 16, p. 3887-99Article in journal (Refereed)
    Abstract [en]

    Understanding how boundaries and domains of Hox gene expression are determined is critical to elucidating the means by which the embryo is patterned along the anteroposterior axis. We have performed a detailed analysis of the mouse Hoxb4 intron enhancer to identify upstream transcriptional regulators. In the context of an heterologous promoter, this enhancer can establish the appropriate anterior boundary of mesodermal expression but is unable to maintain it, showing that a specific interaction with its own promoter is important for maintenance. Enhancer function depends on a motif that contains overlapping binding sites for the transcription factors NFY and YY1. Specific mutations that either abolish or reduce NFY binding show that it is crucial for enhancer activity. The NFY/YY1 motif is reiterated in the Hoxb4 promoter and is known to be required for its activity. As these two factors are able to mediate opposing transcriptional effects by reorganizing the local chromatin environment, the relative levels of NFY and YY1 binding could represent a mechanism for balancing activation and repression of Hoxb4 through the same site.

  • 24.
    Grebe, Markus
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Plant biology: Unveiling the Casparian strip.2011In: Nature, ISSN 1476-4687, Vol. 473, no 7347, p. 294-5Article in journal (Refereed)
  • 25.
    Hanson, Johannes
    et al.
    Department of Physiological Botany, Evolutionary Biology Center, University of Uppsala.
    Regan, S.
    Engström, P.
    The expression pattern of the homeobox gene ATHB13 reveals a conservation of transcriptional regulatory mechanisms between Arabidopsis and hybrid aspen2002In: Plant Cell Reports, ISSN 0721-7714, E-ISSN 1432-203X, Vol. 21, no 1, p. 81-89Article in journal (Refereed)
    Abstract [en]

    ATHB13 belongs to a family of homeodomain leucine zipper (HDZip) transcription factors in Arabidopsis thaliana. To understand the temporal and spatial distribution of ATHB13 gene expression, we examined the ATHB13 promoter activity by means of fusions to the uidA (GUS, beta-glucuronidase) reporter gene in transgenic plants. The strongest promoter activity was detected in the vasculature of the basal portion of petioles for both rosette leaves and cotyledons and at the base of cauline leaves. Activity was also detected in the stem at the base of the cauline leaf in an area corresponding to the leaf gap in the vasculature. In flowers, promoter activity was also present in the receptacle and in the stigma. Transformation of the same promoter-GUS construct into hybrid aspen (Populus tremula x P. tremuloides) resulted in an analogous expression pattern in the petioles of leaves. The similarity of these expression patterns indicates that the trans-acting factors responsible for ATHB13 expression are conserved between aspen and Arabidopsis. The conserved expression pattern of the highly specific Arabidopsis ATHB13 promoter in hybrid aspen demonstrates the potential utility of Arabidopsis promoters for tissue-specific expression in angiosperm trees.

  • 26.
    Hellström, Lars
    et al.
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. School of Education, Culture and Communication, Mälardalen University, Västerås, Sweden.
    Carlsson, Linus
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. School of Education, Culture and Communication, Mälardalen University, Västerås, Sweden.
    Falster, Daniel S.
    Westoby, Mark
    Brännström, Åke
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Evolution and Ecology Program, International Institute for Applied Systems Analysis, Laxenburg, Austria.
    Branch Thinning and the Large-Scale, Self-Similar Structure of Trees2018In: American Naturalist, ISSN 0003-0147, E-ISSN 1537-5323, Vol. 192, no 1, p. E37-E47Article in journal (Refereed)
    Abstract [en]

    Branch formation in trees has an inherent tendency toward exponential growth, but exponential growth in the number of branches cannot continue indefinitely. It has been suggested that trees balance this tendency toward expansion by also losing branches grown in previous growth cycles. Here, we present a model for branch formation and branch loss during ontogeny that builds on the phenomenological assumption of a branch carrying capacity. The model allows us to derive approximate analytical expressions for the number of tips on a branch, the distribution of growth modules within a branch, and the rate and size distribution of tree wood litter produced. Although limited availability of data makes empirical corroboration challenging, we show that our model can fit field observations of red maple (Acer rubrum) and note that the age distribution of discarded branches predicted by our model is qualitatively similar to an empirically observed distribution of dead and abscised branches of balsam poplar (Populus balsamifera). By showing how a simple phenomenological assumptionthat the number of branches a tree can maintain is limitedleads directly to predictions on branching structure and the rate and size distribution of branch loss, these results potentially enable more explicit modeling of woody tissues in ecosystems worldwide, with implications for the buildup of flammable fuel, nutrient cycling, and understanding of plant growth.

  • 27. Hopkins, Brian
    et al.
    Rönnqvist, Louise
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Facilitating postural control: effects on the reaching behavior of 6‐month‐old infants2002In: Developmental Psychobiology, ISSN 0012-1630, E-ISSN 1098-2302, Vol. 40, no 2, p. 168-182Article in journal (Refereed)
    Abstract [en]

    In this study, 3-D kinematic as well as 2-D videorecordings were made of the reaching behavior of infants aged about 6 months who were not yet able to sit. Detailed analyses of these recordings were directed toward specifying the effects of providing additional postural support to the lower body on the spatial and temporal features of such behavior. To detect these effects, reaching and associated head movements in this modified condition were compared to those made while the infants sat in an age-appropriate and commercially available chair lacking the supplementation of support for the pelvic region and upper legs. Findings consistent with predictions included better head stabilization and smoother reaching movements when the infants were in the modified chair. In addition, these two achievements were negatively related to reaching experience. These, and other findings, underscore the infrequently investigated supposition that changes in postural control induce improvements in the control of reaching movements during infancy. Recommendations are made about how the procedure adopted in the present study could be used in subsequent research to give further insights into the codevelopment of posture and action.

  • 28. Hopkins, Brian
    et al.
    Rönnqvist, Louise
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Human handedness: developmental, and evolutionary perspectives1998In: The development of sensory, motor and cognitive capacities in early infancy: from perception to cognition / [ed] George Butterworth and Francesca Simion, Hove, East Sussex, UK: Psychology Press, 1998, p. 191-236Chapter in book (Refereed)
    Abstract [en]

    Argues (1) that handedness in humans has a greater evolutionary depth than speech and language and perhaps even habitual bipedalism, (2) that the developmental origins of handedness are based on different mechanisms than for speech and language, (3) that there is no simple task (e.g., reaching) that will provide a valid index of handedness during the 1st year, (4) that studies on the development of handedness need to be more sensitive to the roles of task and S variables, and (5) that the development of handedness should be addressed by models that incorporate hand preference into different modes of bimanual coordination. Topics discussed include: the ontology of handedness, the evolutionary origins of handedness, the developmental origins of human handedness, and the development of handedness in newborns and beyond.

  • 29. Huang, Jie
    et al.
    Liu, Ying
    Filas, Benjamen
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Beebe, David C.
    Negative and positive auto-regulation of BMP expression in early eye development2015In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 407, no 2, p. 256-264Article in journal (Refereed)
    Abstract [en]

    Previous results have shown that Bone Morphogenetic Protein (BMP) signaling is essential for lens specification and differentiation. How BMP signals are regulated in the prospective lens ectoderm is not well defined. To address this issue we have modulated BMP activity in a chicken embryo pre-lens ectoderm explant assay, and also studied transgenic mice, in which the type I BMP receptors, Bmpr1a and Acvr1, are deleted from the prospective lens ectoderm. Our results show that chicken embryo pre-lens ectoderm cells express BMPs and require BMP signaling for lens specification in vitro, and that in vivo inhibition of BMP signals in the mouse prospective lens ectoderm interrupts lens placode formation and prevents lens invagination. Furthermore, our results provide evidence that BMP expression is negatively auto-regulated in the lens-forming ectoderm, decreasing when the tissue is exposed to exogenous BMPs and increasing when BMP signaling is prevented. In addition, eyes lacking BMP receptors in the prospective lens placode develop coloboma in the adjacent wild type optic cup. In these eyes, Bmp7 expression increases in the ventral optic cup and the normal dorsal-ventral gradient of BMP signaling in the optic cup is disrupted. Pax2 becomes undetectable and expression of Sfrp2 increases in the ventral optic cup, suggesting that increased BMP signaling alter their expression, resulting in failure to close the optic fissure. In summary, our results suggest that negative and positive auto-regulation of BMP expression is important to regulate early eye development. 

  • 30.
    Jidigam, Vijay Kumar
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    BMP - a key signaling molecule in specification and morphogenesis of sensory structures2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cranial placodes are transient thickenings of the vertebrate embryonic head ectoderm that will give rise to sensory (olfactory, lens, and otic) and non-sensory (hypophyseal) components of the peripheral nervous system (PNS). In most vertebrate embryos, these four sensory placodes undergo invagination. Epithelial invagination is a morphological process in which flat cell sheets transform into three-dimensional structures, like an epithelial pit/cup. The process of invagination is crucial during development as it plays an important role for the formation of the lens, inner ear, nasal cavity, and adenohypophysis. Using the chick as the model system the following questions were addressed. What signals are involved in placode invagination? Is there any common regulatory molecular mechanism for all sensory placode invagination, or is it controlled by unique molecular codes for each individual placode? Are placode invagination and acquisition of placode-specific identities two independent developmental processes or coupled together? To address this we used in vivo assays like electroporation and whole embryo culture. Our in vivo results provide evidence that RhoA and F-actin rearrangements, apical constriction, cell elongation and epithelial invagination are regulated by a common BMP (Bone morphogenetic protein) dependent molecular mechanism. In addition, our results show that epithelial invagination and acquisition of placode-specific identities are two independent developmental processes.

    BMP signals have been shown to be essential for lens development and patterning of the retina. However, the spatial and temporal requirement of BMP activity during early events of lens development has remained elusive. Moreover, when and how retinal cells are specified, and whether the lens plays any role for the early development of the retina is not completely known. To address these questions, we have used gain- and loss-of-function analyses in chick explant and intact embryo assays. Here, we show that during lens development BMP activity is both required and sufficient to induce the lens specific marker, L-Maf. After the L-Maf upregulation the cells are no longer dependent on BMP signaling for the next step of fiber cell differentiation, which is characterized by up-regulation of δ-crystallin expression. Regarding the specification of retinal cells our results provide evidence that at blastula stages, BMP signals inhibit the acquisition of eye-field character. Furthermore, from optic vesicle stages, BMP signals emanating from the lens are essential for maintaining eye-field identity, inhibiting telencephalic character and inducing neural retina cells.

  • 31.
    Kolterud, Åsa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    The Role of Lhx2 During Organogenesis: - Analysis of the Hepatic, Hematopoietic and Olfactory Systems2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    During embryonic development a variety of tissues and organs such as the lung, eye, and kidney are being formed. The generation of functional organs is regulated by reciprocal cell-cell interactions. Via the secretion of soluble molecules one type of cells affect the fate of their neighboring cells. A central issue in organogenesis is how a cell interprets such extrinsic signals and adopts a specific fate, and how the cell in response to this signal establishes reciprocal signaling. Transcription factors play a critical role in this process and my thesis focuses on the role of the LIM-homeodomain transcription factor, Lhx2, in the development of three different organ systems, the liver, the hematopoietic system and the olfactory system.

    The liver is formed from endoderm of the ventral foregut and mesenchyme of the septum transversum (st) and its development depends upon signaling interactions between these two tissues. As the liver becomes a distinct organ it is colonized by hematopoietic cells and serves as hematopoietic organ until birth. The fetal liver provides a microenvironment that supports the expansion of the entire hematopoietic system (HS) including the hematopoietic stem cells (HSCs). Liver development in Lhx2-/- embryos is disrupted leading to a lethal anemia due to insufficient support of hematopoiesis. To further investigate the role of Lhx2 in liver development I analyzed gene expression from the Lhx2 locus during liver development in wild-type and Lhx2-/- mice. Lhx2 is expressed in the liver associated st mesenchymal cells that become integrated in the liver and contribute to a subpopulation of hepatic stellate cells in adult liver. Lhx2 is not required for the formation of these mesenchymal cells, suggesting that the phenotype in Lhx2-/- livers is due to the presence of defective mesenchymal cells. The putative role of Lhx2 in the expansion of the HS was examined by introducing Lhx2 cDNA into embryonic stem cells differentiated in vitro. This approach allowed for the generation of immortalized multipotent hematopoietic progenitor cell (HPC) lines that share many characteristics with normal HSCs. The Lhx2-dependent generation of HSC-like cell lines suggests that Lhx2 plays a role in the maintenance and/or expansion of the HS. To isolate genes putatively linked to Lhx2 function, genes differentially expressed in the HPC lines were isolated using a cDNA subtraction approach. This allowed for the identification of a few genes putatively linked to Lhx2 function, as well as several stem cell-specific genes. The antagonist of Wnt signalling, Dickkopf-1 (Dkk-1), was identified in the former group of genes as it showed a similar expression pattern in the fetal liver, as that of Lhx2 and expression of Dkk-1 in fetal liver and in HPC lines appeared to be regulated by Lhx2. This suggests that Dkk-1 plays a role in liver development and/or HSC physiology during embryonic development.

    During development of the olfactory epithelium (OE) neuronal progenitors differentiate into mature olfactory sensory neurons (OSNs) that are individually specified into over a thousand different subpopulations, each expressing a unique odorant receptor (OR) gene. The expression of Lhx2 in olfactory neurons suggested a potential role for Lhx2 in the development of OSNs. To address this OE from Lhx2-/- and wild-type mice was compared. In the absence of functional Lhx2 neuronal differentiation was arrested prior to onset of OR expression. Lhx2 is thus required for the development of OSN progenitors into functional, individually specified OSNs.

    Thus, Lhx2 trigger a variety of cellular responses in different organ systems that play important roles in organ development in vivo and stem cell expansion in vitro.

  • 32.
    Kolterud, Åsa
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Alenius, Mattias
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The Lim homeobox gene Lhx2 is required for olfactory sensory neuron identity2004In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 131, no 21, p. 5319-5326Article in journal (Refereed)
    Abstract [en]

    Progenitor cells in the mouse olfactory epithelium generate over a thousand subpopulations of neurons, each expressing a unique odorant receptor (OR) gene. This event is under the control of spatial cues, since neurons in different epithelial regions are restricted to express region-specific subsets of OR genes. We show that progenitors and neurons express the LIM-homeobox gene Lhx2 and that neurons in Lhx2-null mutant embryos do not diversify into subpopulations expressing different OR genes and other region-restricted genes such as Nqo1 and Ncam2. Lhx2-/- embryos have, however, a normal distribution of Mash1-positive and neurogenin 1-positive neuronal progenitors that leave the cell cycle, acquire pan-neuronal traits and form axon bundles. Increased cell death in combination with increased expression of the early differentiation marker Neurod1, as well as reduced expression of late differentiation markers (Galphaolf and Omp), suggests that neuronal differentiation in the absence of Lhx2 is primarily inhibited at, or immediate prior to, onset of OR expression. Aberrant regional expression of early and late differentiation markers, taken together with unaltered region-restricted expression of the Msx1 homeobox gene in the progenitor cell layer of Lhx2-/- embryos, shows that Lhx2 function is not required for all aspects of regional specification of progenitors and neurons. Thus, these results indicate that a cell-autonomous function of Lhx2 is required for differentiation of progenitors into a heterogeneous population of individually and regionally specified mature olfactory sensory neurons.

  • 33.
    Kremnev, Dmitry
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Get in tune: chloroplast and nucleus harmony2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Photosynthetic eukaryots emerged as a result of several billion years of evolution between proeukaryotic cell and ancestral cyanobacteria that formed modern chloroplasts. The symbiotic relationship led to significant rearrangements in the genomes of the plastid and the nucleus: as many as 90 % of all the plastid genes were transferred to the nucleus. The gene transfer has been accompanied by the development of sophisticated regulatory signaling networks originating in the organelle (retrograde) and in the nucleus (anterograde) that coordinate development of the plastid and ensure adequate cell responses to stress signals. In this thesis I have demonstrated that transcriptional activity of PEP in the chloroplast is essential for proper embryo and seedling development in Arabidopsis thaliana. The function of PEP is dependent on the nuclear encoded PEPassociated factor PRIN2 that is able to sense the redox status of the plastid during seedling development and different stress. In response to the plastid status PRIN2 modulates the transcription activity of the PEP enzyme complex. We further established that PRIN2, as an essential component for full PEP activity, is also required to emit the Plastid Gene Expression (PGE) retrograde signal to regulate the Photosynthesis-Associated Nuclear Genes (PhANG) in the nucleus during early seedling growth via GUN1. On the other hand, regulation of PhANG expression during the High Light (HL) conditions requires functional PRIN2 and PEP activity but is GUN1-independent. Another retrograde signal produced by the developing chloroplast is associated with the tetrapyrrole biosynthesis pathway. We have established that accumulation of the chlorophyll intermediate MgProtoIX-ME in the crd mutant triggers repression of the PhANG expression, and this negative signal is mediated by a cytoplasmic protein complex containing the PAPP5 phosphatase. The nuclear targets that receive the tetrapyrrole mediated signal are GLK1 and GLK2 transcription factors that control the PhANG expression and the expression of the enzymes involved in the biosynthesis of chlorophyll.

  • 34.
    Kuzhandaivel, Anujaianthi
    et al.
    Linköpings universitet, Avdelningen för cellbiologi.
    Schultz, Sebastian W.
    Linköpings universitet, Avdelningen för cellbiologi.
    Alkhori, Liza
    Linköpings universitet, Avdelningen för cellbiologi.
    Alenius, Mattias
    Linköpings universitet, Avdelningen för cellbiologi.
    Cilia-Mediated Hedgehog Signaling in Drosophila2014In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 7, no 3, p. 672-680Article in journal (Refereed)
    Abstract [en]

    Cilia mediate Hedgehog (Hh) signaling in vertebrates and Hh deregulation results in several clinical manifestations, such as obesity, cognitive disabilities, developmental malformations, and various cancers. Drosophila cells are nonciliated during development, which has led to the assumption that cilia-mediated Hh signaling is restricted to vertebrates. Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. We demonstrate that several fundamental key aspects of the vertebrate cilia pathway, such as ciliary localization of Smoothened and the requirement of the intraflagellar transport system, are present in Drosophila. We show that Cos2 and Fused are required for the ciliary transport of Smoothened and that cilia mediate the expression of the Hh pathway target genes. Taken together, our data demonstrate that Hh signaling in Drosophila can be mediated by two pathways and that the ciliary Hh pathway is conserved from Drosophila to vertebrates.

  • 35. Kvarnryd, Moa
    et al.
    Grabic, Roman
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Brandt, Ingvar
    Berg, Cecilia
    Early life progestin exposure causes arrested oocyte development, oviductal agenesis and sterility in adult Xenopus tropicalis frogs2011In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 103, no 1-2, p. 18-24Article in journal (Refereed)
    Abstract [en]

    Levonorgestrel (LNG) is a commonly used pharmaceutical progestin found in the environment. Information on the long-term toxicity of progestins following early life exposure is scant. We investigated the effects of developmental LNG exposure on sex differentiation, reproductive organ development and fertility in the model frog Xenopus tropicalis. Tadpoles were exposed to 0, 0.06 or 0.5 nM LNG via the water from hatching until metamorphosis. At metamorphosis effects on gonadal differentiation were evaluated using a subsample of frogs. Remaining animals were held unexposed for nine months, at which time reproductive organ structure, function and fertility were determined. LNG exposure severely impaired oviduct and ovary development and fertility. All adult females in the 0.5 nM group (n =10) completely lacked oviducts. They also displayed a significantly larger fraction of immature oocytes, arrested in meiotic prophase, than control females. Upon mating with unexposed males, only one of 11 LNG-exposed females laid eggs, whereas all control females did. No effects on testicular development, sperm count or male fertility were observed. At metamorphosis, no effects on sex ratio or gonadal histology were evident. The effects on ovarian and oviductal development were detected at adult age but not at metamorphosis, emphasising the importance of investigating the long-term consequences of developmental exposure. This is the first developmental reproductive toxicity study of a progestin in an aquatic vertebrate. Considering that several progestins are present in contaminated surface waters, further investigation into the sensitivity of frogs to progestins is warranted to understand the risk such compounds may pose to wild frog populations.

  • 36. Lara-Ramirez, Ricardo
    et al.
    Perez-Gonzalez, Carlos
    Anselmi, Chiara
    Patthey, Cedric
    Department of Zoology, University of Oxford, 11a Mansfield Road, Oxford OX1 3SZ, UK.
    Shimeld, Sebastian M.
    A Notch-regulated proliferative stem cell zone in the developing spinal cord is an ancestral vertebrate trait2019In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 1, article id UNSP dev166595Article in journal (Refereed)
    Abstract [en]

    Vertebrates have evolved the most sophisticated nervous systems we know. These differ from the nervous systems of invertebrates in several ways, including the evolution of new cell types, and the emergence and elaboration of patterning mechanisms to organise cells in time and space. Vertebrates also generally have many more cells in their central nervous systems than invertebrates, and an increase in neural cell number may have contributed to the sophisticated anatomy of the brain and spinal cord. Here, we study how increased cell number evolved in the vertebrate central nervous system, investigating the regulation of cell proliferation in the lamprey spinal cord. Markers of proliferation show that a ventricular progenitor zone is found throughout the lamprey spinal cord. We show that inhibition of Notch signalling disrupts the maintenance of this zone. When Notch is blocked, progenitor cells differentiate precociously, the proliferative ventricular zone is lost and differentiation markers become expressed throughout the spinal cord. Comparison with other chordates suggests that the emergence of a persistent Notch-regulated proliferative progenitor zone was a crucial step for the evolution of vertebrate spinal cord complexity.

  • 37. Lara-Ramirez, Ricardo
    et al.
    Poncelet, Guillaume
    Patthey, Cedric
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK.
    Shimeld, Sebastian M.
    The structure, splicing, synteny and expression of lamprey COE genes and the evolution of the COE gene family in chordates2017In: Development, Genes and Evolution, ISSN 0949-944X, E-ISSN 1432-041X, Vol. 227, no 5, p. 319-338Article in journal (Refereed)
    Abstract [en]

    COE genes encode transcription factors that have been found in all metazoans examined to date. They possess a distinctive domain structure that includes a DNA-binding domain (DBD), an IPT/TIG domain and a helix-loop-helix (HLH) domain. An intriguing feature of the COE HLH domain is that in jawed vertebrates it is composed of three helices, compared to two in invertebrates. We report the isolation and expression of two COE genes from the brook lamprey Lampetra planeri and compare these to COE genes from the lampreys Lethenteron japonicum and Petromyzon marinus. Molecular phylogenetic analyses do not resolve the relationship of lamprey COE genes to jawed vertebrate paralogues, though synteny mapping shows that they all derive from duplication of a common ancestral genomic region. All lamprey genes encode conserved DBD, IPT/TIG and HLH domains; however, the HLH domain of lamprey COE-A genes encodes only two helices while COE-B encodes three helices. We also identified COE-B splice variants encoding either two or three helices in the HLH domain, along with other COE-A and COE-B splice variants affecting the DBD and C-terminal transactivation regions. In situ hybridisation revealed expression in the lamprey nervous system including the brain, spinal cord and cranial sensory ganglia. We also detected expression of both genes in mesenchyme in the pharyngeal arches and underlying the notochord. This allows us to establish the primitive vertebrate expression pattern for COE genes and compare this to that of invertebrate chordates and other animals to develop a model for COE gene evolution in chordates.

  • 38. Liebsch, Daniela
    et al.
    Juvany, Marta
    Ziolkowska, Agnieszka
    Chrobok, Daria
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Law, Simon R.
    Melkovicová, Helena
    Brouwer, Bastiaan
    Linden, Pernilla
    Delhomme, Nicolas
    Gardeström, Per
    Keech, Olivier
    Metabolic adjustments required for extended leaf longevity under prolonged darkness revealed by a new loss of function allele of PIF52018Manuscript (preprint) (Other academic)
    Abstract [en]

    Senescence is regulated by a complex interplay of factors and regulatory circuits, which may be accelerated or delayed depending on the integrated signals. Using a forward genetic screen in Arabidopsis thaliana, we identified a mutant strongly delayed in its induction of senescence in response to prolonged darkness. This mutant, which corresponds to a novel loss-of-function allele of PIF5 (PHYTOCHROME-INTERACTING FACTOR 5), exhibits even slightly more extended survival of leaves in darkness than the previously reported pif5-3 TDNA knock-out line. In the present study, we additionally aimed at deciphering the metabolic and regulatory processes conferring this enhanced capacity for survival in pif5 mutants. We combined physiological, metabolomic and transcriptomic analyses, and discovered that the extended survival of mutant leaves in darkness was associated with reduced protein degradation, slight differences in amino acid catabolism related gene expression as well as strong reduction of amino acid transporter expression, which coincided with enhanced amino acid accumulation. Our findings suggest that enhanced survival in darkness could be mediated by moderate levels of protein degradation allowing build up and slow usage of amino acids as alternative respiratory substrates, while during irreversible senescence, strong degradative processes, together with enhanced amino acid transport either to the site of their metabolization inside the leaf, or to other organs in the plant, could promote the fast progression of senescence and antagonize survival. Comparative metabolomics and gene expression analyses suggested that the senescence regulatory network downstream of PIF5 organizes these irreversible stages of leaf senescence, promoting autophagy and amino acid export, possibly by direct binding of important senescence promoting factors like ORE1 to the promoters of some of the involved genes. The failure to induce these later stages may prolong the reversible phase of darkening, thus potentially leading to drastically increased viability of individually darkened leaves under darkness for over 2 weeks.

  • 39.
    Lind, Martin I
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Ingvarsson, Pär K
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Johansson, Helena
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Hall, David
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Johansson, Frank
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Gene flow and selection on phenotypic plasticity in an island system of rana temporaria2011In: Evolution, ISSN 0014-3820, E-ISSN 1558-5646, Vol. 65, no 3, p. 684-697Article in journal (Refereed)
    Abstract [en]

    Gene flow is often considered to be one of the main factors that constrains local adaptation in a heterogeneous environment. However, gene flow may also lead to the evolution of phenotypic plasticity. We investigated the effect of gene flow on local adaptation and phenotypic plasticity in development time in island populations of the common frog Rana temporaria which breed in pools that differ in drying regimes. This was done by investigating associations between traits (measured in a common garden experiment) and selective factors (pool drying regimes and gene flow from other populations inhabiting different environments) by regression analyses and by comparing pairwise F(ST) values (obtained from microsatellite analyses) with pairwise Q(ST) values. We found that the degree of phenotypic plasticity was positively correlated with gene flow from other populations inhabiting different environments (among-island environmental heterogeneity), as well as with local environmental heterogeneity within each population. Furthermore, local adaptation, manifested in the correlation between development time and the degree of pool drying on the islands, appears to have been caused by divergent selection pressures. The local adaptation in development time and phenotypic plasticity is quite remarkable, because the populations are young (less than 300 generations) and substantial gene flow is present among islands.

  • 40.
    Liu, Kui
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wahlberg, Patrik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Leonardsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hägglund, Anna-Carin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Annelii
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bodén, Ida
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wibom, Carin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lund, Leif R
    Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Successful ovulation in plasminogen-deficient mice treated with the broad-spectrum matrix metalloproteinase inhibitor galardin.2006In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 295, no 2, p. 615-622Article in journal (Refereed)
    Abstract [en]

    Many studies have suggested the hypothesis that the plasminogen activator (PA) system and the matrix metalloproteinase (MMP) system, either separately or in combination, may provide the proteolytic activity that is required for rupture of the follicular wall at the time of ovulation. Our recent studies on ovulation in plasminogen (plg)-deficient mice have, however, shown that plasmin is not required for normal ovulation, leading us to the hypothesis that MMPs may be a more important source of proteolysis for this process. To investigate the role of MMPs and also the possibility of a functional overlap or synergy between the MMP and PA systems during ovulation, we have studied ovulation efficiency in wild-type and plg-deficient mice treated with the broad-spectrum MMP inhibitor galardin. We found that in both wild-type mice and heterozygous plg-deficient (plg(+/-)) mice that had been treated with galardin prior to ovulation, there was a mild (18-20%) reduction in ovulation efficiency. Surprisingly, galardin treatment of plg-deficient (plg(-/-)) mice only caused an additional 14% reduction in ovulation efficiency as compared to vehicle-treated plg(-/-) mice. Our data therefore suggest that although MMPs may play a role in degradation of the follicular wall, they may not be obligatory for ovulation. In contrast to previous studies on tissue remodeling during wound heating and placental development, we have demonstrated that there is no obvious functional overlap or synergy between the PA and MMP systems, which has previously been thought to be essential for the ovulatory process.

  • 41. Liu, Y X
    et al.
    Hu, Z Y
    Liu, K
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Byrne, S
    Zou, R J
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    d'Lacey, C
    Ockleford, C D
    Localization and distribution of tissue type and urokinase type plasminogen activators and their inhibitors Type 1 and 2 in human and rhesus monkey fetal membranes1998In: Placenta, ISSN 0143-4004, E-ISSN 1532-3102, Vol. 19, no 2-3, p. 171-180Article in journal (Refereed)
    Abstract [en]

    Fetal membranes consist of 10 distinct layers including components of amnion, chorion and decidua, the latter being of maternal origin. They form mechanically integrated sheets capable of retaining amniotic fluid and play an essential role in protecting fetal growth and development in the pregnant uterus. The extracellular matrix, substrate for plasminogen activators (PAs), is an important supportive framework of the fetal membranes. Fetal membranes from women with preterm premature rupture of membranes may differ in their protease activity compared with normal membranes. To identify the presence of PAs and their inhibitors (PAI) and their possible role in the process of fetal membrane rupture, this study investigated the distribution and localization of both protein and mRNA for tissue (t) and urokinase (u) PA and their inhibitors type 1 (PAI-1) and type 2 (PAI-2) in amniochorion of human and rhesus monkey using conventional and confocal immunofluorescence microscopy. In situ hybridization analysis showed that the distribution and localization of mRNAs for tPA, uPA, PAI-1 and PAI-2 were similar in the fetal membranes of human and rhesus monkey; no obvious species difference was observed. Evidence of tPA mRNA was detected in amniotic epithelium, trophoblast cells and nearly all cells of the decidual layer. Strong expression of uPA mRNA was noted in the decidual cells which increased in intensity as the abscission point was approached. Weak staining in chorion laeve trophoblast was also detected. In situ hybridization experiments showed PAI-1 mRNA to be concentrated mainly in the decidual cells, some of which were interposed into the maternal-facing edge of the chorion laeve. Maximal labelling of the decidua occurred towards the zone of abscission. Weak expression of PAI-1 mRNA was also noted in some cells of the chorion laeve. The distribution of PAI-2 mRNA in amniochorion was also concentrated in the cells of the decidual layer, maximum expression of the mRNA was in the level of abscission. No detectable amount of mRNAs for tPA, uPA, PAI-1 and PAI-2 was found in the fibroblast, reticular and spongy layers. Distribution of the proteins of tPA, uPA and PAI-1 in the fetal membranes of these two species was consistent with the distribution of their mRNA. Anti-PAI-2 immunofluorescence was found to be strongly concentrated in the amniotic epithelium, but PAI-2 mRNA was negative in this layer, suggesting that the epithelium-associated PAI-2 is not of epithelial origin. These findings suggest that a local fibrinolysis in fetal membranes generated by precisely balanced expression of PAs and their inhibitors via paracrine or autocrine mechanisms may play an essential role in fetal membrane development, maturation and in membrane rupture. Following an analysis of the distribution and synthesis of activators and inhibitors it was found that they may play a role in abscission during the third stage of labour.

  • 42.
    Madison, Guy
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Human female exogamy is supported by cross-species comparisons: Cause to recognise sex differences in societal policy?2009In: Behavioral and Brain Sciences, ISSN 0140-525X, E-ISSN 1469-1825, Vol. 32, no 5, p. 400-400Article in journal (Refereed)
    Abstract [en]

    A sex difference in the tendency to outbreed (female exogamy) is a premise for the target article's proposed framework, which receives some support by being shared with chimpanzees but not with more distantly related primates. Further empirical support is provided, and it is suggested that recognition of sex differences might improve effective fairness, taking sexual assault as a case in point.

  • 43.
    Maier, Esther
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Early development of the olfactory placode and early rostrocaudal patterning of the caudal neural tube2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The development of the nervous system is a complex process. Cell divisions, cell differentiation and signalling interactions must be tightly regulated. To comprehend the mature nervous system, we have to understand its assembly during development. Two main questions were addressed in this thesis: (1) how is the caudal part of the central nervous system specified and (2) how is the early development of the olfactory placode regulated? By using tissue and whole embryo assays in the chick, we identified signalling molecules involved in these processes and propose possible mechanisms for their function.

    The central nervous system is regionalized along its rostrocaudal axis during development. However, the mechanisms by which cells in the caudal part of the neuraxis acquire rostrocaudal regional identity have been unresolved. We provide evidence that at gastrula stages cells in the caudal neural plate are specified as cells of caudal spinal cord character in response to Wnt and FGF signals and that cells of rostral spinal cord and caudal hindbrain character only emerge later at neurulation stages in response to retinoic acid signalling acting on previously caudalized cells. In the hindbrain and spinal cord distinct motor neuron subtypes differentiate at precise rostrocaudal positions from progenitor cells. We provide evidence that cells in the caudal neural plate have acquired sufficient positional information to differentiate into motor neurons of the correct rostrocaudal subtype.

    The olfactory placode gives rise to all the structures of the peripheral olfactory system, which, in the chick consists of the olfactory nerve, the sensory epithelium, where the olfactory sensory neurons (OSN) are located and the respiratory epithelium, that produces the mucus. Several studies have addressed the role of signalling cues in the specification of OSNs but much less is known about the regulation of sensory versus respiratory patterning and the events controlling early neurogenesis in the developing olfactory placode.

    We show that by stage 14 the olfactory placode is specified to give rise to both cells of sensory and respiratory epithelial character. Moreover, cells of respiratory epithelial character require BMP signalling, whereas cells of sensory epithelial character require FGF signalling. We suggest a mechanism in which FGF and BMP signals act in an opposing manner to regulate olfactory versus respiratory epithelial cell fate decision. BMP signalling has also been implicated in the regulation of neurogenesis in the sensory epithelium, and we show that BMP signals are required for the generation of OSNs, because in the absence of BMP signalling cells in the sensory epithelium do not mature.

    Independently, we also analyzed the role of Notch signalling during early olfactory development both in vitro and in vivo and provide evidence that active Notch signalling is required to prevent cells in the olfactory placode from premature differentiation.

  • 44.
    Maier, Esther
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Dynamic expression of neurogenic markers in the developing chick epitheliumManuscript (Other academic)
  • 45.
    Maier, Esther
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    von Hofsten, Jonas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Opposing activities of FGF and BMP regulate the olfactory sensory versus respiratory epithelial cell fate decisionManuscript (Other academic)
  • 46. Marchant, Alan
    et al.
    Bhalerao, Rishikesh
    Casimiro, Ilda
    Eklöf, Jan
    Department of Forest Genetics and Plant Physiology, The Swedish University of Agricultural Sciences, S-901 83, Umeå, Sweden.
    Casero, Pedro J
    Bennett, Malcolm
    Sandberg, Goran
    AUX1 promotes lateral root formation by facilitating indole-3-acetic acid distribution between sink and source tissues in the Arabidopsis seedling2002In: The Plant Cell, ISSN 1040-4651, E-ISSN 1532-298X, Vol. 14, no 3, p. 589-597Article in journal (Refereed)
    Abstract [en]

    Arabidopsis root architecture is regulated by shoot-derived signals such as nitrate and auxin. We report that mutations in the putative auxin influx carrier AUX1 modify root architecture as a result of the disruption in hormone transport between indole-3-acetic acid (IAA) source and sink tissues. Gas chromatography-selected reaction monitoring-mass spectrometry measurements revealed that the aux1 mutant exhibited altered IAA distribution in young leaf and root tissues, the major IAA source and sink organs, respectively, in the developing seedling. Expression studies using the auxin-inducible reporter IAA2::uidA revealed that AUX1 facilitates IAA loading into the leaf vascular transport system. AUX1 also facilitates IAA unloading in the primary root apex and developing lateral root primordium. Exogenous application of the synthetic auxin 1-naphthylacetic acid is able to rescue the aux1 lateral root phenotype, implying that root auxin levels are suboptimal for lateral root primordium initiation in the mutant.

  • 47. Meinert, M
    et al.
    Malmström, A
    Tufvesson, E
    Westergren-Thorsson, G
    Petersen, AC
    Laurent, Claude
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Uldbjerg, N
    Eriksen, GV
    Labour induces increased concentrations of biglycan and hyaluronan in human fetal membranes2007In: Placenta, ISSN 0143-4004, E-ISSN 1532-3102, Vol. 28, no 5-6, p. 482-486Article in journal (Refereed)
    Abstract [en]

    Objective: The proteoglycan decorin stabilizes collagen whereas biglycan and hyaluronan disrupt well-organized collagen. The aim was to compare hyaluronan and proteoglycans in human fetal membranes obtained before and after spontaneous labour at term.

    Study design: Prelabour samples of fetal membranes (N = 9) were obtained from elective caesarean sections and regionally sampled from over the cervix (cervical membranes) and mid-zone samples between this area and the placental edge. Postlabour samples (N = 11) were obtained from spontaneous vaginal delivery and also regionally sampled. Amnion and chorio-decidua were analysed separately. The proteoglycans decorin and biglycan were analysed using alcian blue precipitation, SDS polyacrylamide gel electrophoresis and immunostaining. Hyaluronan was analysed using a radioimmunoassay and by histochemistry. Collagen was measured by estimating hydroxyproline content.

    Results: In prelabour membranes the biglycan concentration (mu g/mg wtw) in the cervical amnion was 40% lower than in the mid-zone amnion (P < 0.05). After delivery the cervical amnion showed a twofold increase in biglycan (P < 0.05), a 30% decrease in collagen (P < 0.05), and a 50% decrease in decorin concentration (P < 0.05). In mid-zone samples after delivery the concentrations of hyaluronan showed an increase form 1.0 to 4.9 mu g/mg wtw (P < 0.05). Histology demonstrated a gelatinous substance, which separated amnion and chorio-decidua, in particular at the cervical site. This gelatinous substance contained hyaluronan at a concentration of 3.0 mu g/mg wtw.

    Conclusion: It is well established that prelabour fetal membranes are considerably stronger than postlabour fetal membranes. Two features may explain this; a weakening of the amnion combined with a separation of amnion and chorio-decidua. The biomechanical changes are consistent with the decrease in collagen and decorin, and the increase in hyaluronan and biglycan demonstrated in this study. The separation of the membranes is caused by the formation of a gelatinous substance, rich in hyaluronan. The results indicate that the biomechanical changes are not merely secondary to the stress of labour but that an active maturation process is involved.

  • 48. Mikolajewski, Dirk J
    et al.
    De Block, Marjan
    Rolff, Jens
    Johansson, Frank
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Beckerman, Andrew P
    Stoks, Robby
    Predator-driven trait diversification in a dragonfly genus: covariation in behavioral and morphological antipredator defense2010In: Evolution, ISSN 0014-3820, E-ISSN 1558-5646, Vol. 64, no 11, p. 3327-3335Article in journal (Refereed)
    Abstract [en]

    Proof for predation as an agent shaping evolutionary trait diversification is accumulating, however, our understanding how multiple antipredator traits covary due to phenotypic differentiation is still scarce. Species of the dragonfly genus Leucorrhinia underwent shifts from lakes with fish as top predators to fishless lakes with large dragonfly predators. This move to fishless lakes was accompanied by a partial loss and reduction of larval spines. Here, we show that Leucorrhinia also reduced burst swimming speed and its associated energy fuelling machinery, arginine kinase activity, when invading fishless lakes. This results in patterns of positive phylogenetic trait covariation between behavioral and morphological antipredator defense (trait cospecialization) and between behavioral antipredator defense and physiological machinery (trait codependence). Across species patterns of trait covariation between spine status, burst swimming speed and arginine kinase activity also matched findings within the phenotypically plastic L. dubia. Our results highlight the importance of predation as a factor affecting patterns of multiple trait covariation during phenotypic diversification.

  • 49. Modig, Carina
    et al.
    Modesto, Teresa
    Canario, Adelino
    Cerda, Joan
    von Hofsten, Jonas
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Olsson, Per-Erik
    Molecular characterization and expression pattern of zona pellucida proteins in gilthead seabream (Sparus aurata)2006In: Biology of Reproduction, ISSN 0006-3363, E-ISSN 1529-7268, Vol. 75, no 5, p. 717-725Article in journal (Refereed)
    Abstract [en]

    The developing oocyte is surrounded by an acellular envelope that is composed of 2-4 isoforms of zona pellucida (ZP) proteins. The ZP proteins comprise the ZP1, ZP2, ZP3, and ZPX isoforms. While ZP1 (ZPB) and ZP3 (ZPC) are present in all species, ZP2 (ZPA) is not found in teleost fish and ZPX is not found in mammals. In the present study, we identify and characterize the ZP1, ZP3 and ZPX isoforms of gilthead seabream. Furthermore, by analyzing the conserved domains, which include the external hydrophobic patch and the internal hydrophobic patch, we show that ZP2 and ZPX are closely related isoforms. ZP proteins are synthesized in either the liver or ovary of most teleosts. Only in rainbow trout has it been shown that zp3 has dual transcription sites. In gilthead seabream, all four mRNA isoforms are transcribed in both the liver and ovary, with zp1a, zp1b, and zp3 being highly expressed in the liver, and zpx being primarily expressed in the ovary. However, determination of the ZP proteins in plasma showed high levels of ZP1b, ZP3, and ZPX, with low or non-detectable levels of ZP1a. In similarity to other teleost ZPs, the hepatic transcription of all four ZP isoforms is under estrogenic control. Previously, we have shown that cortisol can potentiate estrogen-induced ZP synthesis in salmonids, and now we show that this is not the case in the gilthead seabream. The present study shows for the first time the endocrine regulation of a teleost ZPX isoform, and demonstrates the dual-organ transcriptional activities of all the ZP proteins in one species.

  • 50.
    Monroe, Melanie J
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Does competition drive character differences between species on a macroevolutionary scale?2012In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 25, no 11, p. 2341-2347Article in journal (Refereed)
    Abstract [en]

    Sympatric sister species generally have a degree of phenotypic differentiation that allows them to coexist. It has been well documented that phenotypic similarity results, through resource competition, in one of two major outcomes: local extinction of either competitor or character displacement. Limiting similarity suggests that there is a maximum degree of phenotypic niche overlap with which similar species may coexist. Breaching that maximum would result in exclusion. Character displacement, on the other hand, implies that the species differentiate phenotypically so that resource competition is reduced to the point where coexistence is possible. While it has been suggested that these theories have the potential to accelerate (character displacement) or limit phenotypic evolution (competitive exclusion) on microevolutionary time scales, their effects on macroevolution remain under-studied. If competition accelerates evolution on a macroevolutionary scale, one would expect that phenotypic diversity increases as novel species push aside existing species. On the other hand, one might also expect that phenotypic evolution comes to a halt as novel species are trapped in the (ever decreasing) phenotypic space not yet occupied by existing species, except at the extremes of the phenotypic spectrum. Studying the current geographical ranges of more than 3000 extant species representing 29 mammalian families and their respective body masses, I found little evidence of competition accelerating body size differentiation between species.

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