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sequoia controls the type I>0 daughter proliferation switch in the developing Drosophila nervous system
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.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0001-5095-541X
2016 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 143, no 20, 3774-3784 p.Article in journal (Refereed) Published
Abstract [en]

Neural progenitors typically divide asymmetrically to renew themselves, while producing daughters with more limited potential. In the Drosophila embryonic ventral nerve cord, neuroblasts initially produce daughters that divide once to generate two neurons/glia (type I proliferation mode). Subsequently, many neuroblasts switch to generating daughters that differentiate directly (type 0). This programmed type I>0 switch is controlled by Notch signaling, triggered at a distinct point of lineage progression in each neuroblast. However, how Notch signaling onset is gated was unclear. We recently identified Sequoia (Seq), a C2H2 zinc-finger transcription factor with homology to Drosophila Tramtrack (Ttk) and the positive regulatory domain (PRDM) family, as important for lineage progression. Here, we find that seq mutants fail to execute the type I>0 daughter proliferation switch and also display increased neuroblast proliferation. Genetic interaction studies reveal that seq interacts with the Notch pathway, and seq furthermore affects expression of a Notch pathway reporter. These findings suggest that seq may act as a context-dependent regulator of Notch signaling, and underscore the growing connection between Seq, Ttk, the PRDM family and Notch signaling.

Place, publisher, year, edition, pages
The Company of Biologists Ltd , 2016. Vol. 143, no 20, 3774-3784 p.
Keyword [en]
Lineage tree, Cell cycle, Asymmetric division, Combinatorial control, Notch
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology Cell Biology Medical Biotechnology
Identifiers
URN: urn:nbn:se:liu:diva-132739DOI: 10.1242/dev.139998PubMedID: 27578794OAI: oai:DiVA.org:liu-132739DiVA: diva2:1048761
Available from: 2016-11-22 Created: 2016-11-22 Last updated: 2016-12-08Bibliographically approved
In thesis
1. 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 anyorgan system, consisting of billions of neurons, of numerous cell sub-types, interconnectedin a vast network. Given this enormous complexity, decoding the genetic programscontrolling the multistep process of CNS development remains a major challenge. Whilegreat progress has been made with respect to understanding sub-type specification,considerably less is known regarding how the generation of the precise number of eachsub-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 (Print) (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: 2016-11-30Bibliographically approved

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The full text will be freely available from 2017-10-15 10:27
Available from 2017-10-15 10:27

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