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Specification of unique neuronal sub-types by integration of positional and temporal cues
Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
2010 (English)Doctoral 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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2010. , 102 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1211
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-63628ISBN: 978-91-7393-306-3 (print)OAI: oai:DiVA.org:liu-63628DiVA: diva2:381787
Public defence
2010-12-03, Linden, Universitetssjukhuset, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2010-12-28 Created: 2010-12-28 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, E-ISSN 1545-7885, 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: 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
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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: 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.

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: 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
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(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: 2016-11-30

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