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  • 1.
    Baumgardt, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Genetic mechanisms behind cell specification in the Drosophila CNS2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The human central nervous system (CNS) contains a daunting number of cells and tremendous cellular diversity. A fundamental challenge of developmental neurobiology is to address the questions of how so many different types of neurons and glia can be generated at the precise time and place, making precisely the right connections. Resolving this issue involves dissecting the elaborate genetic networks that act within neurons and glia, as well as in the neural progenitor cells that generates them, to specify their identities.

    My PhD project has involved addressing a number of unresolved issues pertaining to how neural progenitor cells are specified to generate different types of neurons and glial cells in different temporal and spatial domains, and also how these early temporal and spatial cues are integrated to activate late cell fate determinants, which act in post-mitotic neural cells to activate distinct batteries of terminal differentiation genes.

    Analyzing the development of a specific Drosophila melanogaster (Drosophila) CNS stem cell – the neuroblast 5-6 (NB5-6) – we have identified several novel mechanisms of cell fate specification in the Drosophila CNS. We find that, within this lineage, the differential specification of a group of sequentially generated neurons – the Ap cluster neurons – is critically dependent upon the simultaneous triggering of two opposing feed-forward loops (FFLs) within the neuroblast. The first FFL involves cell fate determinants and progresses within the post-mitotic neurons to establish a highly specific combinatorial code of regulators, which activates a distinct battery of terminal differentiation genes. The second loop, which progresses in the neuroblast, involves temporal and sub-temporal genes that together oppose the progression of the first FFL. This leads to the establishment of an alternative code of regulators in late-born Ap cluster neurons, whereby alternative cell fates are specified. Furthermore, we find that the generation and specification of the Ap cluster neurons is modulated along the neuraxis by two different mechanisms. In abdominal segments, Hox genes of the Bithorax cluster integrates with Pbx/Meis factors to instruct NB5-6 to leave the cell cycle before the Ap cluster neurons are generated. In brain segments, Ap cluster neuron equivalents are generated, but improperly specified due to the absence of the proper Hox and temporal code. Additionally, in thoracic segments we find that the specification of the Ap cluster neurons is critically dependent upon the integration of the Hox, Pbx/Meis, and the temporal genes, in the activation of the critical cell fate determinant FFL.

    We speculate that the developmental principles of (i) feed-forward combinatorial coding; (ii) simultaneously triggered yet opposing feed-forward loops; and (iii) integration of different Hox, Pbx/Meis, and temporal factors, at different axial levels to control inter-segmental differences in lineage progression and specification; might be used widely throughout the animal kingdom to generate cell type diversity in the CNS.

    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 genetic cascade involving the genes klumfuss, nab and castor specifies the abdominal leucokinergic neurons in the Drosophila CNS
    Open this publication in new window or tab >>A genetic cascade involving the genes klumfuss, nab and castor specifies the abdominal leucokinergic neurons in the Drosophila CNS
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The genetic mechanisms underlying the specification of a large number of different cell fates starting from a limited group of progenitor cells are a major focus of investigations of central nervous system development. In Drosophila the identities of the different neuronal progenitor cells, the neuroblasts, are specified by a combination of spatial and temporal factors. But how each neuroblast gives rise to a specific repertoire of cell types via a precise programme is poorly understood. In this report we analyse the specification of a small set of peptidergic cells, the abdominal leucokinergic neurons. We identify the progenitors of these neurons, the temporal window in which they are specified, and the influence of the Notch signalling pathway on their specification. We also show that the products of the genes klumfuss, nab and castor play important roles in their specification via a genetic cascade.

    Keywords
    Drosophila, CNS development, neuronal fate specification, Leucokinin, ABLK
    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:liu:diva-51644 (URN)
    Available from: 2009-11-11 Created: 2009-11-11 Last updated: 2016-11-30Bibliographically approved
  • 2.
    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.

  • 3.
    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)
  • 4.
    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.

  • 5.
    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.

  • 6.
    Benito-Sipos, Jonathan
    et al.
    University of Autonoma.
    Estacio, Alicia
    CSIC, Spain.
    Moris, Marta
    CSIC, Spain.
    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.
    Diaz-Benjumea , Fernando J
    CSIC, Spain.
    Analysis of the specification of the Leucokininergic cell fate2009In: 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. S16-S16Conference paper (Refereed)
  • 7.
    Benito-Sipos, Jonathan
    et al.
    University Autonoma of Madrid.
    Estacio-Gomez, Alicia
    University Autonoma of Madrid.
    Moris-Sanz, Marta
    University Autonoma of Madrid.
    Baumgardt, Magnus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE.
    Thor, Stefan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE.
    J Diaz-Benjumea, Fernando
    University Autonoma of Madrid.
    A genetic cascade involving klumpfuss, nab and castor specifies the abdominal leucokinergic neurons in the Drosophila CNS2010In: DEVELOPMENT, ISSN 0950-1991, Vol. 137, no 19, p. 3327-3336Article in journal (Refereed)
    Abstract [en]

    Identification of the genetic mechanisms underlying the specification of large numbers of different neuronal cell fates from limited numbers of progenitor cells is at the forefront of developmental neurobiology. In Drosophila, the identities of the different neuronal progenitor cells, the neuroblasts, are specified by a combination of spatial cues. These cues are integrated with temporal competence transitions within each neuroblast to give rise to a specific repertoire of cell types within each lineage. However, the nature of this integration is poorly understood. To begin addressing this issue, we analyze the specification of a small set of peptidergic cells: the abdominal leucokinergic neurons. We identify the progenitors of these neurons, the temporal window in which they are specified and the influence of the Notch signaling pathway on their specification. We also show that the products of the genes klumpfuss, nab and castor play important roles in their specification via a genetic cascade.

  • 8.
    Benito-Sipos, Jonathan
    et al.
    Centro de Biología Molecular-Severo Ochoa, Universidad Autónoma de Madrid-C.S.I.C., Madrid, Spain.
    Estacio-Gómez, Alicia
    Centro de Biología Molecular-Severo Ochoa, Universidad Autónoma de Madrid-C.S.I.C., Madrid, Spain.
    Moris-Sanz, Marta
    Centro de Biología Molecular-Severo Ochoa, Universidad Autónoma de Madrid-C.S.I.C., Madrid, Spain.
    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.
    Díaz-Benjumea, Fernando J.
    Centro de Biología Molecular-Severo Ochoa, Universidad Autónoma de Madrid-C.S.I.C., Madrid, Spain.
    A genetic cascade involving the genes klumfuss, nab and castor specifies the abdominal leucokinergic neurons in the Drosophila CNSManuscript (preprint) (Other academic)
    Abstract [en]

    The genetic mechanisms underlying the specification of a large number of different cell fates starting from a limited group of progenitor cells are a major focus of investigations of central nervous system development. In Drosophila the identities of the different neuronal progenitor cells, the neuroblasts, are specified by a combination of spatial and temporal factors. But how each neuroblast gives rise to a specific repertoire of cell types via a precise programme is poorly understood. In this report we analyse the specification of a small set of peptidergic cells, the abdominal leucokinergic neurons. We identify the progenitors of these neurons, the temporal window in which they are specified, and the influence of the Notch signalling pathway on their specification. We also show that the products of the genes klumfuss, nab and castor play important roles in their specification via a genetic cascade.

  • 9.
    Benito-Sipos, Jonathan
    et al.
    University of Autonoma Madrid, Spain.
    Ulvklo, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Gabilondo, Hugo
    University of Autonoma Madrid, Spain.
    Baumgardt, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Angel, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Torroja, Laura
    University of Autonoma Madrid, Spain.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Seven up acts as a temporal factor during two different stages of neuroblast 5-6 development2011In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 138, no 24, p. 5311-5320Article in journal (Refereed)
    Abstract [en]

    Drosophila embryonic neuroblasts generate different cell types at different time points. This is controlled by a temporal cascade of Hb -greater than Kr -greater than Pdm -greater than Cas -greater than Grh, which acts to dictate distinct competence windows sequentially. In addition, Seven up (Svp), a member of the nuclear hormone receptor family, acts early in the temporal cascade, to ensure the transition from Hb to Kr, and has been referred to as a switching factor. However, Svp is also expressed in a second wave within the developing CNS, but here, the possible role of Svp has not been previously addressed. In a genetic screen for mutants affecting the last-born cell in the embryonic NB5-6T lineage, the Ap4/FMRFamide neuron, we have isolated a novel allele of svp. Expression analysis shows that Svp is expressed in two distinct pulses in NB5-6T, and mutant analysis reveals that svp plays two distinct roles. In the first pulse, svp acts to ensure proper downregulation of Hb. In the second pulse, which occurs in a Cas/Grh double-positive window, svp acts to ensure proper sub-division of this window. These studies show that a temporal factor may play dual roles, acting at two different stages during the development of one neural lineage.

  • 10.
    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.

  • 11.
    Losada-Perez, Maria
    et al.
    University Autonoma Madrid.
    Gabilondo, Hugo
    University Autonoma Madrid.
    del Saz, Delia
    University Autonoma Madrid.
    Baumgardt, Magnus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology.
    Molina, Isabel
    University Autonoma Madrid.
    Leon, Yolanda
    University Autonoma Madrid.
    Monedero, Ignacio
    University Autonoma Madrid.
    Torroja, Laura
    University Autonoma Madrid.
    Benito-Sipos, Jonathan
    University Autonoma Madrid.
    Lineage-unrelated neurons generated in different temporal windows and expressing different combinatorial codes can converge in the activation of the same terminal differentiation gene in JOURNAL OF NEUROGENETICS, vol 24, issue , pp 80-802010In: JOURNAL OF NEUROGENETICS, Informa Healthcare , 2010, Vol. 24, p. 80-80Conference paper (Refereed)
    Abstract [en]

    n/a

  • 12.
    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

  • 13.
    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

  • 14.
    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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