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Genetic mechanisms behind cell specification in the Drosophila CNS
Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
2009 (English)Doctoral 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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2009. , 104 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1157
Keyword [en]
Drosophila melanogaster, nervous system development, cell specification, stem cells, cell proliferation, combinatorial coding, feedforward loop
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:liu:diva-51637ISBN: 978-91-7393-483-1 (print)OAI: oai:DiVA.org:liu-51637DiVA: diva2:276178
Public defence
2009-12-04, Hörsal Linden, Campus US, Linköpings universitet, Linköping, 00:00 (English)
Opponent
Supervisors
Available from: 2009-11-13 Created: 2009-11-11 Last updated: 2016-11-30Bibliographically approved
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.
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2007 (English)In: PLoS biology, ISSN 1544-9173, Vol. 5, no 2, 0295-0308 p.Article 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: 2016-11-30Bibliographically 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
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2009 (English)In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 139, no 5, 969-982 p.Article 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
Keyword
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: 2016-11-30Bibliographically 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.

Keyword
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: 2016-11-30Bibliographically 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
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(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.

Keyword
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

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