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Evolutionarily conserved anterior expansion of the central nervous system promoted by a common PcG-Hox program
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.
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2018 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 7, article id dev160747Article in journal (Refereed) Published
Abstract [en]

A conserved feature of the central nervous system (CNS) is the prominent expansion of anterior regions (brain) compared with posterior (nerve cord). The cellular and regulatory processes driving anterior CNS expansion are not well understood in any bilaterian species. Here, we address this expansion in Drosophila and mouse. We find that, compared with the nerve cord, the brain displays extended progenitor proliferation, more elaborate daughter cell proliferation and more rapid cell cycle speed in both Drosophila and mouse. These features contribute to anterior CNS expansion in both species. With respect to genetic control, enhanced brain proliferation is severely reduced by ectopic Hox gene expression, by either Hox misexpression or by loss of Polycomb group (PcG) function. Strikingly, in PcG mutants, early CNS proliferation appears to be unaffected, whereas subsequent brain proliferation is severely reduced. Hence, a conserved PcG-Hox program promotes the anterior expansion of the CNS. The profound differences in proliferation and in the underlying genetic mechanisms between brain and nerve cord lend support to the emerging concept of separate evolutionary origins of these two CNS regions.

Place, publisher, year, edition, pages
Cambridge, United Kingdom: The Company of Biologists Ltd. , 2018. Vol. 145, no 7, article id dev160747
Keywords [en]
Asymmetric division, Cell cycle, Combinatorial control, Evolution of the CNS, Lineage size, Nervous system development
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:liu:diva-147741DOI: 10.1242/dev.160747ISI: 000438944000010PubMedID: 29530878Scopus ID: 2-s2.0-85045513794OAI: oai:DiVA.org:liu-147741DiVA, id: diva2:1204692
Available from: 2018-05-09 Created: 2018-05-09 Last updated: 2018-12-10Bibliographically approved
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: 2019-09-30Bibliographically approved

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Yaghmaeian Salmani, BehzadMonedero Cobeta, IgnacioRakar, JonathanBauer, SusanneRodriguez Curt, JesúsStarkenberg, AnnikaThor, Stefan

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