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  • 1.
    Baumgardt, Magnus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Terriente, Javier
    Division of Developmental Neuroscience, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom.
    Díaz-Benjumea, Fernando J.
    Centro de Biología Molecular-Severo Ochoa/C.S.I.C., Universidad Autónoma-Cantoblanco, Madrid 28049, Spain.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Neuronal Subtype Specification within a Lineage by Opposing Temporal Feed-Forward Loops2009In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 139, no 5, p. 969-982Article in journal (Refereed)
    Abstract [en]

    Neural progenitors generate distinct cell types at different stages, but the mechanisms controlling these temporal transitions are poorly understood. In the Drosophila CNS, a cascade of transcription factors, the ‘temporal gene cascade’, has been identified, that acts to alter progenitor competence over time. However, many CNS lineages display broad temporal windows, and it is unclear how broad windows progress into sub-windows that generate unique cell types. We have addressed this issue in an identifiable Drosophila CNS lineage, and find that a broad castor temporal window is sub-divided by two different feed-forward loops, both of which are triggered by castor itself. The first loop acts to specify a unique cell fate, while the second loop suppresses the first loop, thereby allowing for the generation of alternate cell fates. This mechanism of temporal and ‘sub-temporal’ genes acting in opposing feed-forward loops may be used by many stem cell lineages to generate diversity.

  • 2.
    Baumgardt, Magnus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology-IKE . Linköping University, Faculty of Health Sciences.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology-IKE . Linköping University, Faculty of Health Sciences.
    Terriente, Javier
    University of Autonoma.
    J Diaz-Benjumea, Fernando
    University of Autonoma.
    Thor , Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology-IKE . Linköping University, Faculty of Health Sciences.
    From stem cell to unique neuron: Temporal transitions in an identified CNS progenitor cell by feedforward combinatorial coding2009In: The 12th European Drosophila Neurobiology Conference 6-10 September 2008 Wuerzburg, Germany: in: Journal of Neurogenetics, Volume 23 Supplement 1 2009, 2009, Vol. 23, p. S14-S15Conference paper (Refereed)
  • 3.
    Baumgardt, Magnus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Yaghmaeian Salmani, Behzad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Bivik, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    MacDonald, Ryan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Gunnar, Erika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade2014In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 30, no 2, p. 192-208Article in journal (Refereed)
    Abstract [en]

    During central nervous system (CNS) development, progenitors typically divide asymmetrically, renewing themselves while budding off daughter cells with more limited proliferative potential. Variation in daughter cell proliferation has a profound impact on CNS development and evolution, but the underlying mechanisms remain poorly understood. We find that Drosophila embryonic neural progenitors (neuroblasts) undergo a programmed daughter proliferation mode switch, from generating daughters that divide once (type I) to generating neurons directly (type 0). This typelgreater than0 switch is triggered by activation of Dacapo (mammalian p21(CIP1)/p27(KIP1)/p57(Kip2)) expression in neuroblasts. In the thoracic region, Dacapo expression is activated by the temporal cascade (castor) and the Hox gene Antennapedia. In addition, castor, Antennapedia, and the late temporal gene grainyhead act combinatorially to control the precise timing of neuroblast cell-cycle exit by repressing Cyclin E and E2f. This reveals a logical principle underlying progenitor and daughter cell proliferation control in the Drosophila CNS.

  • 4.
    Baumgardt, Magnus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Miguel-Aliaga, Irene
    Medical Research Council National Institute for Medical Research, London,.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Ekman, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Specification of neuronal identities by feedforward combinatorial coding.2007In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 5, no 2, p. 0295-0308Article in journal (Refereed)
    Abstract [en]

    Neuronal specification is often seen as a multistep process: earlier regulators confer broad neuronal identity and are followed by combinatorial codes specifying neuronal properties unique to specific subtypes. However, it is still unclear whether early regulators are re-deployed in subtype-specific combinatorial codes, and whether early patterning events act to restrict the developmental potential of postmitotic cells. Here, we use the differential peptidergic fate of two lineage-related peptidergic neurons in the Drosophila ventral nerve cord to show how, in a feedforward mechanism, earlier determinants become critical players in later combinatorial codes. Amongst the progeny of neuroblast 5-6 are two peptidergic neurons: one expresses FMRFamide and the other one expresses Nplp1 and the dopamine receptor DopR. We show the HLH gene collier functions at three different levels to progressively restrict neuronal identity in the 5-6 lineage. At the final step, collier is the critical combinatorial factor that differentiates two partially overlapping combinatorial codes that define FMRFamide versus Nplp1/DopR identity. Misexpression experiments reveal that both codes can activate neuropeptide gene expression in vast numbers of neurons. Despite their partially overlapping composition, we find that the codes are remarkably specific, with each code activating only the proper neuropeptide gene. These results indicate that a limited number of regulators may constitute a potent combinatorial code that dictates unique neuronal cell fate, and that such codes show a surprising disregard for many global instructive cues.

  • 5.
    Ekdahl, Christer
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Karlsson, Daniel
    Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, Faculty of Health Sciences.
    Wigertz, Ove
    Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Forsum, Urban
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    A study of the usage of a decision-support system for infective endocarditis2000In: Medical informatics and the Internet in medicine (Print), ISSN 1463-9238, E-ISSN 1464-5238, Vol. 25, no 1, p. 1-18Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to examine a design for a World Wide Web-based decision-support system in use by clinically active physicians. A prototype implementation of the design concerned management of infective endocarditis patient cases. The design was based on an integration of hypertext and rule-based knowledge. In the study sessions, physicians in the field of internal medicine worked on managing authentic patient cases in a laboratory setting. Data was collected from interviews with the physicians using video recordings and stimulated recall technique. The qualitative data was analysed according to the constant comparative method in order to develop a model of the physicians' usage of the system. The resulting model describes perceived contributions and criteria for usefulness of the system. The ways the physicians used the system showed that it was able to provide patient-specific support for confirming clinical decisions, for higher-level patient management, and for preparing for and initiating expert consultations. Users also stated that new medical knowledge could be gained as a side effect of using the system.

  • 6.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Specification of unique neuronal sub-types by integration of positional and temporal cues2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The nervous system contains vast numbers of neuronal sub-types, generated at specific time points, in the proper location, and in proper numbers. One of the fundamental issues in neurobiology is to understand the molecular genetic mechanisms that underlie the generation of this daunting neuronal diversity.

    To help shed light upon these fundamental questions, my PhD project has addressed the generation and specification of a certain group of neurons, the Ap cluster. This group of four neurons is found only in thoracic segments within the Drosophila melanogaster central nervous system, and consists of three different cell types. Mapping of the neuroblast (stem cell) that generates the Ap cluster neurons, neuroblast 5-6, and the highly restricted appearance of this cluster allowed me to address the following questions: How does NB 5-6 change its temporal competence over time to generate the Ap cluster neurons late in the lineage, and how is temporal competence altered to ensure diversity among the Ap neurons? What are the mechanisms that allow these Ap cluster neurons to emerge only in the thoracic segments?

    My studies have helped identify a number of mechanisms acting to specify the Ap cluster neurons. One type of mechanism involves several of different feed-forward loops that play out during NB 5-6 lineage development. These are triggered within the stem cell, where the temporal gene castor activates a number of genes. These castor targets are subsequently involved in several regulatory feed-forward loops, that ultimately result in the unique combinatorial expression of cell fate determinants in the different Ap neurons, which in turn ultimately lead to the activation of unique terminal differentiation genes. In addition, I have identified three different mechanisms by which the NB 5-6 lineage is modulated along the neuroaxis. In the abdomen I find that an early cell cycle exit is initiated by the Bx-C gene members and Pbx/Meis cofactors, which result in the truncation of the NB 5-6 lineage, preventing the Ap cluster neurons from being generated. In thoracic segments Hox, Pbx/Meisand temporal genes act in concert to specify Ap cluster neurons, by integrating with the castor temporal gene. In anterior segments, improper Hox and temporal coding results in a failure to specify bona fide Ap cluster neurons, even though equivalents of Ap cluster neurons are generated.

    In summary, my thesis work has helped identify a number of mechanisms acting to specify this unique neuronal sub-type, including: feed-forward combinatorial coding, opposing feed-forward loops and integrated temporal/Hox mediated specification throughout different axial levels. I suggest that these mechanisms may be widely used within the animal kingdom, hence contributing to the great cellular diversity observed within the central nervous system of most animal species.

    List of papers
    1. Specification of neuronal identities by feedforward combinatorial coding.
    Open this publication in new window or tab >>Specification of neuronal identities by feedforward combinatorial coding.
    Show others...
    2007 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 5, no 2, p. 0295-0308Article in journal (Refereed) Published
    Abstract [en]

    Neuronal specification is often seen as a multistep process: earlier regulators confer broad neuronal identity and are followed by combinatorial codes specifying neuronal properties unique to specific subtypes. However, it is still unclear whether early regulators are re-deployed in subtype-specific combinatorial codes, and whether early patterning events act to restrict the developmental potential of postmitotic cells. Here, we use the differential peptidergic fate of two lineage-related peptidergic neurons in the Drosophila ventral nerve cord to show how, in a feedforward mechanism, earlier determinants become critical players in later combinatorial codes. Amongst the progeny of neuroblast 5-6 are two peptidergic neurons: one expresses FMRFamide and the other one expresses Nplp1 and the dopamine receptor DopR. We show the HLH gene collier functions at three different levels to progressively restrict neuronal identity in the 5-6 lineage. At the final step, collier is the critical combinatorial factor that differentiates two partially overlapping combinatorial codes that define FMRFamide versus Nplp1/DopR identity. Misexpression experiments reveal that both codes can activate neuropeptide gene expression in vast numbers of neurons. Despite their partially overlapping composition, we find that the codes are remarkably specific, with each code activating only the proper neuropeptide gene. These results indicate that a limited number of regulators may constitute a potent combinatorial code that dictates unique neuronal cell fate, and that such codes show a surprising disregard for many global instructive cues.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-50010 (URN)10.1371/journal.pbio.0050037 (DOI)
    Note
    Original Publication: Magnus Baumgardt, Irene Miguel-Aliaga, Daniel Karlsson, Helen Ekman and Stefan Thor, Specification of neuronal identities by feedforward combinatorial coding., 2007, PLoS biology, (5), 2, e37. http://dx.doi.org/10.1371/journal.pbio.0050037 Licensee: PLoS Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-12Bibliographically approved
    2. Neuronal Subtype Specification within a Lineage by Opposing Temporal Feed-Forward Loops
    Open this publication in new window or tab >>Neuronal Subtype Specification within a Lineage by Opposing Temporal Feed-Forward Loops
    Show others...
    2009 (English)In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 139, no 5, p. 969-982Article in journal (Refereed) Published
    Abstract [en]

    Neural progenitors generate distinct cell types at different stages, but the mechanisms controlling these temporal transitions are poorly understood. In the Drosophila CNS, a cascade of transcription factors, the ‘temporal gene cascade’, has been identified, that acts to alter progenitor competence over time. However, many CNS lineages display broad temporal windows, and it is unclear how broad windows progress into sub-windows that generate unique cell types. We have addressed this issue in an identifiable Drosophila CNS lineage, and find that a broad castor temporal window is sub-divided by two different feed-forward loops, both of which are triggered by castor itself. The first loop acts to specify a unique cell fate, while the second loop suppresses the first loop, thereby allowing for the generation of alternate cell fates. This mechanism of temporal and ‘sub-temporal’ genes acting in opposing feed-forward loops may be used by many stem cell lineages to generate diversity.

    Place, publisher, year, edition, pages
    Cambridge,MA, USA: Cell Press, 2009
    Keywords
    neural progenitor, temporal transitions, feed-forward loops, combinatorial codes, cell fate specification
    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:liu:diva-51638 (URN)10.1016/j.cell.2009.10.032 (DOI)000272169400020 ()
    Note

    Original Publication: Magnus Baumgardt, Daniel Karlsson, Javier Terriente, Fernando J. Díaz-Benjumea and Stefan Thor, Neuronal Subtype Specification within a Lineage by Opposing Temporal Feed-Forward Loops, 2009, Cell, (139), 5, 969-982. http://dx.doi.org/10.1016/j.cell.2009.10.032 Copyright: Elsevier Science B.V., Amsterdam. http://www.cell.com/cellpress

    Available from: 2009-11-11 Created: 2009-11-11 Last updated: 2017-12-12Bibliographically approved
    3. Segment-specific Neuronal Sub-type Specification by the Integration of Anteroposterior and Temporal Cues
    Open this publication in new window or tab >>Segment-specific Neuronal Sub-type Specification by the Integration of Anteroposterior and Temporal Cues
    2010 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 8, no 5Article in journal (Refereed) Published
    Abstract [en]

    The generation of distinct neuronal sub-types at different axial levels relies upon both anteroposterior and temporal cues. However, the integration between these cues is poorly understood. In the Drosophila CNS, the segmentally repeated neuroblast 5-6 generates a unique group of neurons, the Apterous cluster, only in thoracic segments. Recent studies have identified elaborate genetic pathways acting to control the generation of these neurons. These insights, combined with novel markers, provide a unique opportunity for addressing how anteroposterior and temporal cues are integrated to generate segment-specific neuronal sub-types. We find that Pbx/Meis, Hox and temporal genes act in three different ways. Posteriorly, Pbx/Meis and posterior Hox genes block lineage progression within an early temporal window, by triggering cell cycle exit. Because Ap neurons are generated late in the thoracic 5-6 lineage, this prevents generation of Ap cluster cells in the abdomen. Thoracically, Pbx/Meis and anterior Hox genes integrate with late temporal genes to specify Ap clusters, via activation of a specific feed-forward loop. In brain segments, ‘Ap cluster cells’ are present but lack both proper Hox and temporal coding. Only by simultaneously altering Hox and temporal gene activity in all segments can Ap clusters be generated throughout the neuroaxis. This study provides the first detailed analysis of an identified neuroblast lineage along the entire neuroaxis, and provides novel insight into how Hox/Pbx/Meis anteroposterior cues are integrated with temporal cues. It reveals a surprisingly restricted yet multifaceted function of the anteroposterior cues with respect to lineage control and cell fate specification.

    Keywords
    anteroposterior patterning, temporal transitions, Hox, Pbx/Meis, cell specification
    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:liu:diva-51641 (URN)10.1371/journal.pbio.1000368 (DOI)000278759600005 ()
    Note
    Original Publication: Daniel Karlsson, Magnus Baumgardt and Stefan Thor, Segment-specific Neuronal Sub-type Specification by the Integration of Anteroposterior and Temporal Cues, 2010, PLoS biology, (8), 5. http://dx.doi.org/10.1371/journal.pbio.1000368 Licensee: Public Library of Science http://www.plos.org/ Available from: 2009-11-11 Created: 2009-11-11 Last updated: 2017-12-12Bibliographically approved
    4. A structurally plastic extension of the homeodomain recognition helix orchestrates central Hox protein activity
    Open this publication in new window or tab >>A structurally plastic extension of the homeodomain recognition helix orchestrates central Hox protein activity
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Protein function is encoded within the amino acid coding sequence and the variation in this sequence, and subsequent structure, provide the bases for functional diversification at the molecular and organismal levels. However, how separate protein domainscooperate to build protein activity remains largely unknown. Focusing on three domains of central Hox transcription factors, we mutagenized combinations of their domains to investigate their intrinsic functional organization. Our results demonstrate a high degree of domain interactivity, with an orchestrating role of a structurally plastic C-terminal extension of the homeodomain (HD). This domain provides, in a folding dependant manner, a topologically constrained contact with the Hox cofactor Extradenticle, which impacts the positioning of the recognition helix in the major groove of DNA. These findings provide novel insights in HD/DNA target recognition and, given the phylogeny of this C-terminal extension, also shed light on the molecular bases underlying the functional diversification of paralogous Hox families.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-63627 (URN)
    Available from: 2010-12-28 Created: 2010-12-28 Last updated: 2019-12-30
  • 7.
    Karlsson, Daniel
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE.
    Aspevall, O
    Linkoping Univ, S-58183 Linkoping, Sweden Karolinska Inst, Dept Immunol Microbiol Pathol & Infect Dis, Stockholm, Sweden Linkoping Univ, Div Clin Microbiol, S-58183 Linkoping, Sweden.
    Forsum, Urban
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology .
    A decision-support system for urinary tract infections1999In: JAMIA Journal of the American Medical Informatics Association, ISSN 1067-5027, E-ISSN 1527-974X, p. 1094-1094Conference paper (Other academic)
  • 8.
    Karlsson, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Baumgardt, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Segment-specific Neuronal Sub-type Specification by the Integration of Anteroposterior and Temporal Cues2010In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 8, no 5Article in journal (Refereed)
    Abstract [en]

    The generation of distinct neuronal sub-types at different axial levels relies upon both anteroposterior and temporal cues. However, the integration between these cues is poorly understood. In the Drosophila CNS, the segmentally repeated neuroblast 5-6 generates a unique group of neurons, the Apterous cluster, only in thoracic segments. Recent studies have identified elaborate genetic pathways acting to control the generation of these neurons. These insights, combined with novel markers, provide a unique opportunity for addressing how anteroposterior and temporal cues are integrated to generate segment-specific neuronal sub-types. We find that Pbx/Meis, Hox and temporal genes act in three different ways. Posteriorly, Pbx/Meis and posterior Hox genes block lineage progression within an early temporal window, by triggering cell cycle exit. Because Ap neurons are generated late in the thoracic 5-6 lineage, this prevents generation of Ap cluster cells in the abdomen. Thoracically, Pbx/Meis and anterior Hox genes integrate with late temporal genes to specify Ap clusters, via activation of a specific feed-forward loop. In brain segments, ‘Ap cluster cells’ are present but lack both proper Hox and temporal coding. Only by simultaneously altering Hox and temporal gene activity in all segments can Ap clusters be generated throughout the neuroaxis. This study provides the first detailed analysis of an identified neuroblast lineage along the entire neuroaxis, and provides novel insight into how Hox/Pbx/Meis anteroposterior cues are integrated with temporal cues. It reveals a surprisingly restricted yet multifaceted function of the anteroposterior cues with respect to lineage control and cell fate specification.

  • 9.
    MacDonald, Ryan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ulvklo, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Bivik, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Baumgardt, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Notch Mediates a Genetic Switch in Neural Lineage Topology in DEVELOPMENTAL BIOLOGY, vol 356, issue 1, pp 227-2272011In: DEVELOPMENTAL BIOLOGY, Elsevier Science B.V., Amsterdam , 2011, Vol. 356, no 1, p. 227-227Conference paper (Refereed)
    Abstract [en]

    n/a

  • 10.
    Merabet, S.
    et al.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    Litim, I.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    Foos, N.
    AFMB, Université de la Méditerranée, Parc Scientifique de LuminyMarseille Cedex 09, France.
    Jesus Mate, M.
    AFMB, Université de la Méditerranée, Parc Scientifique de LuminyMarseille Cedex 09, France.
    Dixit, R.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Saadaoui, M.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    Vincentelli, R.
    AFMB, Université de la Méditerranée, Parc Scientifique de LuminyMarseille Cedex 09, France.
    Monier, B.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Vijayraghavan, K.
    Perrin, L.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    Pradel, J.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    Cambillau, C.
    AFMB, Université de la Méditerranée, Parc Scientifique de LuminyMarseille Cedex 09, France.
    Ortiz Lombardia, M.
    AFMB, Université de la Méditerranée, Parc Scientifique de LuminyMarseille Cedex 09, France.
    Graba, Y.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    A structurally plastic extension of the homeodomain recognition helix orchestrates central Hox protein activityManuscript (preprint) (Other academic)
    Abstract [en]

    Protein function is encoded within the amino acid coding sequence and the variation in this sequence, and subsequent structure, provide the bases for functional diversification at the molecular and organismal levels. However, how separate protein domainscooperate to build protein activity remains largely unknown. Focusing on three domains of central Hox transcription factors, we mutagenized combinations of their domains to investigate their intrinsic functional organization. Our results demonstrate a high degree of domain interactivity, with an orchestrating role of a structurally plastic C-terminal extension of the homeodomain (HD). This domain provides, in a folding dependant manner, a topologically constrained contact with the Hox cofactor Extradenticle, which impacts the positioning of the recognition helix in the major groove of DNA. These findings provide novel insights in HD/DNA target recognition and, given the phylogeny of this C-terminal extension, also shed light on the molecular bases underlying the functional diversification of paralogous Hox families.

  • 11.
    Merabet, Samir
    et al.
    Université de la Méditerranée, Marseille, France.
    Litim-Mecheri, Isma
    Université de la Méditerranée, Marseille, France.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Dixit, Richa
    Tata Institute of Fundamental Research, Bangalore, India.
    Saadaoui, Mehdi
    Université de la Méditerranée, Marseille, France.
    Monier, Bruno
    Université de la Méditerranée, Marseille, France.
    Brun, Christine
    Université de la Méditerranée, Marseille, France.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Vijayraghavan, K
    Tata Institute of Fundamental Research, Bangalore, India.
    Perrin, Laurent
    Université de la Méditerranée, Marseille, France.
    Pradel, Jacques
    Université de la Méditerranée, Marseille, France.
    Graba, Yacine
    Université de la Méditerranée, Marseille, France.
    Insights into Hox Protein Function from a Large Scale Combinatorial Analysis of Protein Domains2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 10Article in journal (Refereed)
    Abstract [en]

    Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA), we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences.

  • 12.
    Thor, Stefan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology.
    Baumgardt, Magnus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology.
    Karlsson, Daniel
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology.
    From progenitor to unique neuron Neuronal sub-type specification by the integration of positional and temporal cues in INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE, vol 28, issue 8, pp 671-6712010In: INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE, Elsevier Science B.V., Amsterdam. , 2010, Vol. 28, no 8, p. 671-671Conference paper (Refereed)
    Abstract [en]

    n/a

  • 13.
    Ulvklo, Carina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    MacDonald, Ryan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Bivik, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Baumgardt, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression2012In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 139, no 4, p. 678-689Article in journal (Refereed)
    Abstract [en]

    During neural lineage progression, differences in daughter cell proliferation can generate different lineage topologies. This is apparent in the Drosophila neuroblast 5-6 lineage (NB5-6T), which undergoes a daughter cell proliferation switch from generating daughter cells that divide once to generating neurons directly. Simultaneously, neural lineages, e.g. NB5-6T, undergo temporal changes in competence, as evidenced by the generation of different neural subtypes at distinct time points. When daughter proliferation is altered against a backdrop of temporal competence changes, it may create an integrative mechanism for simultaneously controlling cell fate and number. Here, we identify two independent pathways, Prospero and Notch, which act in concert to control the different daughter cell proliferation modes in NB5-6T. Altering daughter cell proliferation and temporal progression, individually and simultaneously, results in predictable changes in cell fate and number. This demonstrates that different daughter cell proliferation modes can be integrated with temporal competence changes, and suggests a novel mechanism for coordinately controlling neuronal subtype numbers.

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