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Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
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2014 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 30, no 2, p. 192-208Article in journal (Refereed) Published
Abstract [en]

During central nervous system (CNS) development, progenitors typically divide asymmetrically, renewing themselves while budding off daughter cells with more limited proliferative potential. Variation in daughter cell proliferation has a profound impact on CNS development and evolution, but the underlying mechanisms remain poorly understood. We find that Drosophila embryonic neural progenitors (neuroblasts) undergo a programmed daughter proliferation mode switch, from generating daughters that divide once (type I) to generating neurons directly (type 0). This typelgreater than0 switch is triggered by activation of Dacapo (mammalian p21(CIP1)/p27(KIP1)/p57(Kip2)) expression in neuroblasts. In the thoracic region, Dacapo expression is activated by the temporal cascade (castor) and the Hox gene Antennapedia. In addition, castor, Antennapedia, and the late temporal gene grainyhead act combinatorially to control the precise timing of neuroblast cell-cycle exit by repressing Cyclin E and E2f. This reveals a logical principle underlying progenitor and daughter cell proliferation control in the Drosophila CNS.

Place, publisher, year, edition, pages
Elsevier (Cell Press) , 2014. Vol. 30, no 2, p. 192-208
National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:liu:diva-109588DOI: 10.1016/j.devcel.2014.06.021ISI: 000339641500012PubMedID: 25073156OAI: oai:DiVA.org:liu-109588DiVA, id: diva2:739449
Available from: 2014-08-21 Created: 2014-08-21 Last updated: 2018-05-09
In thesis
1. Genetic Mechanisms Regulating the Spatiotemporal Modulation of Proliferation Rate and Mode in Neural Progenitors and Daughter Cells during Embryonic CNS Development
Open this publication in new window or tab >>Genetic Mechanisms Regulating the Spatiotemporal Modulation of Proliferation Rate and Mode in Neural Progenitors and Daughter Cells during Embryonic CNS Development
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The central nervous system (CNS) is a hallmark feature of animals with a bilateral symmetry: bilateria and can be sub-divided into the brain and nerve cord. One of the prominent properties of the CNS across bilateria is the discernible expansion of its anterior part (brain) compared with the posterior one (nerve cord). This evolutionarily conserved feature could be attributed to four major developmental agencies: First, the existence of more anterior progenitors. Second, anterior progenitors are more proliferative. Third, anterior daughter cells, generated by the progenitors, are more proliferative. Forth, fewer cells are removed by programmed cell death (PCD) anteriorly. My thesis has addressed these issues, and uncovered both biological principles and genetic regulatory networks that promote these A-P differences. I have used the Drosophila and mouse embryonic CNSs as model systems. Regarding the 1st issue, while the brain indeed contains more progenitors, my studies demonstrate that this only partly explains the anterior expansion. Indeed, with regard to the 2nd issue, my studies, on both the Drosophila and mouse CNS, demonstrate that anterior progenitors divide more extensively. Concerning the 3rd issue, in Drosophila we identified a gradient of daughter proliferation along the AP axis of the developing CNS with brain daughter cells being more proliferative. Specifically, in the brain, progenitors divide to generate a series of daughter cells that divide once (Type I), to generate two neurons or glia. In contrast, in the nerve cord, progenitors switch during later stages, from first generating dividing daughters to subsequently generating daughters that directly differentiate (Type 0). Hence, nerve cord progenitors undergo a programmed Type I->0 proliferation switch. In the Drosophila posterior CNS, this switch occurs earlier and is more prevalent, contributing to the generation of smaller lineages in the posterior regions. Similar to Drosophila, in the mouse brain we also found that progenitor and daughter cell proliferation was elevated and extended into later developmental stages, when compared to the spinal cord. DNA-labeling experiments revealed faster cycling cells in the brain when compared to the nerve cord, in both Drosophila and mouse. In both Drosophila and mouse, we found that the suppression of progenitor and daughter proliferation in the nerve cord is controlled by the Hox homeotic gene family. Hence, the absence of Hox gene expression in the brain provides a logical explanation for the extended progenitor proliferation and lack of Type I->0 switch. The repression of Hox genes in the brain is mediated by the histonemodifying Polycomb Group complex (PcG), which thereby is responsible for the anterior expansion. With respect to the 4th issue, we found no effect of PCD on anterior expansion in Drosophila, while this cannot be asserted for the mouse embryonic neurodevelopment as there are no genetic tools to abolish PCD effectively in mammals. Taken together, the studies presented in this thesis identified global and evolutionarily-conserved genetic programs that promote anterior CNS expansion, and pave the way for understanding the evolution of size along the anterior-posterior CNS axis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 63
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1628
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-147736 (URN)10.3384/diss.diva-147736 (DOI)9789176852774 (ISBN)
Public defence
2018-05-31, Berzeliussalen, Campus US, Linköping, 09:00 (English)
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Available from: 2018-05-09 Created: 2018-05-08 Last updated: 2018-05-09Bibliographically approved

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