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Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression
Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
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2012 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 139, no 4, 678-689 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Company of Biologists , 2012. Vol. 139, no 4, 678-689 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-74790DOI: 10.1242/dev.074500ISI: 000300259800005OAI: oai:DiVA.org:liu-74790DiVA: diva2:495183
Note

funding agencies|Swedish Research Council||Knut and Alice Wallenberg foundation||Swedish Cancer Foundation||

Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2017-12-07
In thesis
1. Genetic mechanisms controlling cell specification and cell numbers in the Drosophila CNS
Open this publication in new window or tab >>Genetic mechanisms controlling cell specification and cell numbers in the Drosophila CNS
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A central theme in developmental neurobiology pertains to how the  diversity of different cell types is generated. In addition, it is equally important to understand how the specific numbers of each cell type is regulated. The developing Drosophila central nervous system (CNS) is a widely used system in which to study the genetic mechanisms underlying these events. Earlier studies have shown that a small number of progenitors produce the daunting number of cells that builds the mature CNS. This is accomplished by a series of events that in an increasingly restricted manner results in different combinatorial transcription factor codes that act to specify the different cell types in the CNS. However the factors controlling the progressive restriction in developmental potential and the ultimate fate of cells have not been completely elucidated.

My PhD project has been focused on a specific stem cell in the embryonic Drosophila CNS, the neuroblast 5-6 (NB 5-6), and the lineage of neural cells that is produced by that stem cell. Earlier work have provided both a lot of knowledge and a multitude of genetic tools regarding this specific stem cell, which allowed us to address these issues at single cell resolution in an identifiable lineage. In particular, a late-born group of neurons expressing the apterous gene, the Apterous neurons, had been extensively studied in the past. One particular Apterous neuron, Ap4, expresses the neuropeptide gene FMRFamide (FMRFa), and the selective expression of this gene makes it a powerful marker for addressing many aspects of NB 5-6 development.

To identify novel genes acting to control neuronal development, a large scale forward genetic screen was performed utilizing an FMRFa-GFP transgenic reporter construct, thereby using a marker that reports perturbations of NB 5-6-lineage development. Flies were treated with EMS, a chemical that induces random point mutations and the progeny where screened for aberrant FMRFa-GFP expression. From a total of ~ 10,000 mutated chromosomes ~600 mutants where isolated and further characterized. One group of mutants displayed additional Apterous neurons when compared to wild type, and a number of them represented new alleles of three previously known genes: neuralized (neur), kuzbanian (kuz), and seven up (svp). Neur and Kuz are parts of the Notch signaling pathway and Svp is the Drosophila COUP-TF1/2 ortholog; an orphan member of the steroid/thyroid receptor superfamily. These findings initiated two separate studies regarding the roles of these genes in the NB 5-6 lineage.

Mutants in the Notch pathway i.e., neur and kuz displayed an excess number of Apterous neurons, born from NB 5-6. We initiated detailed studies regarding the origin of these ectopic neurons and could show that Notch signaling is critical for controlling a switch in proliferation mode in the latter part of the NB 5-6 lineage. With this new mechanism we could independently and simultaneously manipulate cell proliferation and temporal progression, and thereby predictable control cell fate and cell numbers born from the NB 5-6.

The screen further identified additional mechanisms acting to specify the Ap cluster neurons. During NB 5-6 lineage development several temporal transitions acts to specify neurons born in different time windows. The temporal gene castor is expressed in a fairly large temporal window and the Ap neurons are sub-specified during that window by several combinatorial feed forward loops of transcription factors. In the screen, we identified a novel allele of the svp gene. We found that svp acts as a sub-temporal factor, fine-tuning the castor window into three different temporal parts. Previous studies have shown a role for svp earlier in the temporal cascade and we could confirm this in the NB 5-6 lineage. Together these data for the first time identify dual temporal roles of the same gene in a single NB lineage.

In summary, my thesis has helped identify novel genetic mechanisms controlling neuron subtype specification and numbers.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 77 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1299
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76157 (URN)978-91-7519-942-9 (ISBN)
Public defence
2012-04-19, Eken, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2016-11-30Bibliographically approved
2. Genetic pathways controlling CNS development: The role of Notch signaling in regulating daughter cell proliferation in Drosophila
Open this publication in new window or tab >>Genetic pathways controlling CNS development: The role of Notch signaling in regulating daughter cell proliferation in Drosophila
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The human central nervous system (CNS) displays the greatest cellular diversity of any organ system, consisting of billions of neurons, of numerous cell sub-types, interconnected in a vast network. Given this enormous complexity, decoding the genetic programs controlling the multistep process of CNS development remains a major challenge. While great progress has been made with respect to understanding sub-type specification, considerably less is known regarding how the generation of the precise number of each sub-type is controlled.

The aim of this thesis was to gain deeper knowledge into the regulatory programs controlling cell specification and proliferation. To address these questions I have studied the Drosophila embryonic CNS as a model system, to thereby be able to investigate the genetic mechanisms at high resolution. Despite the different size and morphology between the Drosophila and the mammalian CNS, the lineages of their progenitors share similarity. Importantly for this thesis, both species progenitors show elaborate variations in their proliferation modes, either giving rise to daughters that can directly differentiate into neurons or glia (type 0), divide once (type I), or multiple times (type II).

The studies launched off with a comprehensive chemical forward genetic screen, for the very last born cell in the well-studied lineage of progenitor NB5-6T: the Ap4 neuron, which expresses the neuropeptide FMRFa. NB5-6T is a powerful model to use, because it undergoes a programmed type I>0 daughter cell proliferation switch. An FMRF-eGFP transgenic reporter was utilized as readout for successful terminal differentiation of Ap4/FMRFa and thereby proper lineage progression of the ∼20 cells generated. The strongest mutants were mapped to genes with both known and novel essential functions e.g., spatial and temporal patterning, cell cycle control, cell specification and chromatin modification. Subsequently, we focused on some of the genes that showed a loss of function phenotype with an excess of lineage cells. We found that Notch is critical for the type I>0 daughter cell proliferation switch in the NB5-6T lineage and globally as well. When addressing the broader relevance of these findings, and to further decipher the Notch pathway, we discovered that selective groups of E(spl) genes is controlling the switch in a close interplay with four key cell cycle factors: Cyclin E, String, E2F and Dacapo, in most if not all embryonic progenitors. The Notch mediation of the switch is likely to be by direct transcriptional regulation. Furthermore, another gene identified in the screen, sequoia, was investigated. The analysis revealed that sequoia is also controlling the daughter cell switch in the CNS, and this partly through context dependent interactions with the Notch pathway.

Taken together, the findings presented in this thesis demonstrate that daughter cell proliferation switches in Drosophila neural lineages are genetically programmed, and that Notch contributes to the triggering of these events. Given that early embryonic processes is frequently shown to be evolutionary conserved, you can speculate that changeable daughter proliferation programs could be applied to mammals, and contribute to a broader understanding of proliferation processes in humans as well.

 

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. 80 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1542
National Category
Cell and Molecular Biology Cell Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Immunology
Identifiers
urn:nbn:se:liu:diva-132743 (URN)10.3384/diss.diva-132743 (DOI)9789176856659 (ISBN)
Public defence
2016-12-15, Berzeliussalen, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2016-11-22 Created: 2016-11-22 Last updated: 2017-01-13Bibliographically approved

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