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Neural Lineage Progression Controlled by a Temporal Proliferation Program.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0002-2671-3645
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
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2017 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 43, no 3, 332-348 p.Article in journal (Refereed) Published
Abstract [en]

Great progress has been made in identifying transcriptional programs that establish stem cell identity. In contrast, we have limited insight into how these programs are down-graded in a timely manner to halt proliferation and allow for cellular differentiation. Drosophila embryonic neuroblasts undergo such a temporal progression, initially dividing to bud off daughters that divide once (type I), then switching to generating non-dividing daughters (type 0), and finally exiting the cell cycle. We identify six early transcription factors that drive neuroblast and type I daughter proliferation. Early factors are gradually replaced by three late factors, acting to trigger the type I→0 daughter proliferation switch and eventually to stop neuroblasts. Early and late factors regulate each other and four key cell-cycle genes, providing a logical genetic pathway for these transitions. The identification of this extensive driver-stopper temporal program controlling neuroblast lineage progression may have implications for studies in many other systems.less thanbr /greater than (Copyright © 2017 Elsevier Inc. All rights reserved.)

Place, publisher, year, edition, pages
Cell Press , 2017. Vol. 43, no 3, 332-348 p.
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:liu:diva-143117DOI: 10.1016/j.devcel.2017.10.004ISI: 000414584300011PubMedID: 29112852OAI: oai:DiVA.org:liu-143117DiVA: diva2:1158420
Note

Funding agencies: Swedish Research Council [621-2013-5258]; Knut and Alice Wallenberg Foundation [KAW2011.0165, KAW2012.0101]; Swedish Cancer Foundation [140780, 150633]

Available from: 2017-11-20 Created: 2017-11-20 Last updated: 2017-11-20Bibliographically approved
In thesis
1. Genetic mechanisms regulating proliferation and cell specification in the Drosophila embryonic CNS
Open this publication in new window or tab >>Genetic mechanisms regulating proliferation and cell specification in the Drosophila embryonic CNS
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The central nervous system (CNS) consists of an enormous number of cells, and large cellular variance, integrated into an elaborate network. The CNS is the most complex animal organ, and therefore its establishment must be controlled by many different genetic programs. Considering the high level of complexity in the human CNS, addressing issues related to human neurodevelopment represents a major challenge. Since comparative studies have revealed that neurodevelopmental programs are well conserved through evolution, on both the genetic and functional levels, studies on invertebrate neurodevelopmental programs are often translatable to vertebrates. Indeed, the basis of our current knowledge about vertebrate CNS development has been greatly aided by studies on invertebrates, and in particular on the Drosophila melanogaster (fruit fly) model system.

This thesis attempted to identify novel genes regulating neural cell specification and proliferation in the CNS, using the Drosophila model system. Moreover, I aimed to address how those genes govern neural progenitor cells (neuroblasts; NBs) to obtain/maintain their stemness identity and proliferation capacity, and how they drive NBs through temporal windows and series of programmed asymmetric division, which gradually reduces their stemness identity in favor of neural differentiation, resulting in appropriate lineage progression. In the first project, we conducted a forward genetic screen in Drosophila embryos, aimed at isolating genes involved in regulation of neural proliferation and specification, at the single cell resolution. By taking advantage of the restricted expression of the neuropeptide FMRFa in the last-born cell of the NB lineage 5-6T, the Ap4 neuron, we could monitor the entire lineage progression. This screen succeeded in identifying 43 novel genes controlling different aspects of CNS development. One of the genes isolated, Ctr9, displayed extra Ap4/FMRFa neurons. Ctr9 encodes a component of the RNA polymerase II complex Paf1, which is involved in a number of transcriptional processes. The Paf1C, including Ctr9, is highly conserved from yeast to human, and in the past couple of years, its importance for transcription has become increasingly appreciated. However, studies in the Drosophila system have been limited. In the screen, we isolated the first mutant of Drosophila Ctr9 and conducted the first detailed phenotypic study on its function in the Drosophila embryonic CNS. Loss of function of Ctr9 leads to extra NB numbers, higher proliferation ratio and lower expression of neuropeptides. Gene expression analysis identified several other genes regulated by Ctr9, which may explain the Ctr9 mutant phenotypes. In summary, we identified Ctr9 as an essential gene for proper CNS development in Drosophila, and this provides a platform for future study on the Drosophila Paf1C. Another interesting gene isolated in the screen was worniou (wor), a member of the Snail family of transcription factors. In contrast to Ctr9, whichdisplayed additional Ap4/FMRFa neurons, wor mutants displayed a loss of these neurons. Previous studies in our group have identified many genes acting to stop NB lineage progression, but how NBs are pushed to proliferate and generate their lineages was not well known. Since wor may constitute a “driver” of proliferation, we decided to study it further. Also, we identified five other transcription factors acting together with Wor as pro-proliferative in both NBs and their daughter cells. These “drivers” are gradually replaced by the previously identified late-acting “stoppers.” Early and late factors regulate each other and the cell cycle, and thereby orchestrate proper neural lineage progression.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. 68 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1558
National Category
Developmental Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell Biology Genetics Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-134459 (URN)10.3384/diss.diva-134459 (DOI)9789176856055 (ISBN)
Public defence
2017-03-17, Hasselquist, Campus US, Linköping, 09:00 (English)
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Available from: 2017-02-14 Created: 2017-02-14 Last updated: 2017-11-20Bibliographically approved

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