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Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling
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. Linköping University, Faculty of Medicine and Health Sciences. University of Cambridge, England.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Institute Pasteur, France; CNRS, France.
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2016 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 4, e1005984Article in journal (Refereed) Published
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Abstract [en]

The Notch pathway controls proliferation during development and in adulthood, and is frequently affected in many disorders. However, the genetic sensitivity and multi-layered transcriptional properties of the Notch pathway has made its molecular decoding challenging. Here, we address the complexity of Notch signaling with respect to proliferation, using the developing Drosophila CNS as model. We find that a Notch/Su(H)/E(spl)-HLH cascade specifically controls daughter, but not progenitor proliferation. Additionally, we find that different E(spl)-HLH genes are required in different neuroblast lineages. The Notch/Su(H)/E(spl)-HLH cascade alters daughter proliferation by regulating four key cell cycle factors: Cyclin E, String/Cdc25, E2f and Dacapo (mammalian p21(CIP1)/p27(KIP1)/p57(Kip2)). ChIP and DamID analysis of Su(H) and E(spl)-HLH indicates direct transcriptional regulation of the cell cycle genes, and of the Notch pathway itself. These results point to a multi-level signaling model and may help shed light on the dichotomous proliferative role of Notch signaling in many other systems.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE , 2016. Vol. 12, no 4, e1005984
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-128759DOI: 10.1371/journal.pgen.1005984ISI: 000375231900032PubMedID: 27070787OAI: oai:DiVA.org:liu-128759DiVA: diva2:931917
Note

Funding Agencies|Knut and Alice Wallenberg Foundation [KAW2012.0101]; Swedish Research Council [621-2010-5214]; Swedish Cancer Foundation [120531]

Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2017-11-30
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 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
2. Regulatory programs controlling profileration during Drosophila nervous system development
Open this publication in new window or tab >>Regulatory programs controlling profileration during Drosophila nervous system development
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The central nervous system (CNS) is the most complex organ in the body, responsible for complex functions, including thinking, reasoning and memory. The CNS contains cells of many different types, often generated in vast numbers. Hence, CNS development requires precise genetic control of both cell fate and of cell proliferation, to generate the right number of cells, with the proper identity, and in the proper location. The cells also need to make connections with each other for correct signaling and function. This complexity evokes the question of how this is regulated. How does the stem cells, responsible for building the CNS, know how many times to divide, and how does the daughters know which identity to acquire and in which location they shall end up? During Drosophila melanogaster development, the neuroblasts (NBs) are responsible for generating the CNS. In each hemisegment, every NB is unique in identity, and generates a predetermined number of daughters with specific identities. The lineages of different NBs vary in size, but are always the same for each specific NB, and the division modes of each NBs is hence stereotyped. Most NBs start dividing by renewing themselves while generating daughters that will in turn divide once to generate two neurons and/or glia (denoted type I mode). Many, maybe all, NBs later switch to generating daughters that will differentiate directly into a neuron or glia (denoted type 0 mode). This type I>0 switch occurs at different time-points during lineage progression, and influences the total numbers of cells generated from a single NB.

The work presented in this thesis aimed at investigating the genetic regulation of proliferation, with particular focus on the type I>0 switch. In the first project, the implication of the Notch pathway on the type I>0 switch was studied. Mutants of the Notch pathway do not switch, and the results show that the Notch pathway regulates the switch by activation of several target genes, both regulators and cell cycle genes. One of the target genes, the E(spl)-C genes, have been difficult to study due to functional redundancy. This study reveals that even though they can functionally compensate for each other, they have individual functions in different lineages. Regarding cell cycle genes, both Notch and E(spl)-C regulate several key cell cycle genes, and molecular analysis indicated that this regulation is direct. In the second project we studied the seq gene, previously identified in a genetic screen. We found that seq controls the type I>0 switch by regulating the key cell cycle genes, but also through interplay with the Notch pathway. Notch and seq stop proliferation, and in the third project we wanted to identify genes that drive proliferation. We found that there is battery of early NB genes, socalled early factors, which activate the cell cycle, and drive NB and daughter proliferation. These are gradually replaced by late regulators, and the interplay between early and late factors acts to achieve precise control of lineage progression.

The work presented here increases our understanding of how regulatory programs act to control the development of the CNS; to generate the right number of cells of different identities. These results demonstrate the importance of correct regulation of proliferation in both stem cells and daughters. Problems in this control can result in either an underdeveloped CNS or loss of control such as in cancer. Knowledge about these regulatory programs can contribute to the development of therapeutics against these diseases.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. 70 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1540
National Category
Developmental Biology Cell Biology Cell and Molecular Biology Immunology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:liu:diva-133498 (URN)10.3384/diss.diva-133498 (DOI)9789176856819 (ISBN)
Public defence
2017-02-10, Berzeliussalen, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-12-29 Created: 2016-12-29 Last updated: 2017-01-12Bibliographically approved

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Bivik, CarolineMacdonald, RyanGunnar, ErikaThor, Stefan

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