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Genetic Mechanisms Regulating the Spatiotemporal Modulation of Proliferation Rate and Mode in Neural Progenitors and Daughter Cells during Embryonic CNS Development
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
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: urn:nbn:se:liu:diva-147736DOI: 10.3384/diss.diva-147736ISBN: 9789176852774 (print)OAI: oai:DiVA.org:liu-147736DiVA, id: diva2:1204622
Public defence
2018-05-31, Berzeliussalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2018-05-09 Created: 2018-05-08 Last updated: 2019-09-30Bibliographically approved
List of papers
1. Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade
Open this publication in new window or tab >>Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade
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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
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-109588 (URN)10.1016/j.devcel.2014.06.021 (DOI)000339641500012 ()25073156 (PubMedID)
Available from: 2014-08-21 Created: 2014-08-21 Last updated: 2019-03-13
2. Anterior-Posterior Gradient in Neural Stem and Daughter Cell Proliferation Governed by Spatial and Temporal Hox Control
Open this publication in new window or tab >>Anterior-Posterior Gradient in Neural Stem and Daughter Cell Proliferation Governed by Spatial and Temporal Hox Control
2017 (English)In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 27, no 8, p. 1161-1172Article in journal (Refereed) Published
Abstract [en]

A readily evident feature of animal central nervous systems (CNSs), apparent in all vertebrates and many invertebrates alike, is its "wedge-like appearance, with more cells generated in anterior than posterior regions. This wedge could conceivably be established by an antero-posterior (A-P) gradient in the number of neural progenitor cells, their proliferation behaviors, and/or programmed cell death (PCD). However, the contribution of each of these mechanisms, and the underlying genetic programs, are not well understood. Building upon recent progress in the Drosophila melanogaster (Drosophila) ventral nerve cord (VNC), we address these issues in a comprehensive manner. We find that, although PCD plays a role in controlling cell numbers along the A-P axis, the main driver of the wedge is a gradient of daughter proliferation, with divisions directly generating neurons (type 0) being more prevalent posteriorly and dividing daughters (type I) more prevalent anteriorly. In addition, neural progenitor (NB) cell-cycle exit occurs earlier posteriorly. The gradient of type I amp;gt; 0 daughter proliferation switch and NB exit combine to generate radically different average lineage sizes along the A-P axis, differing by more than 3-fold in cell number. We find that the Hox homeotic genes, expressed in overlapping A-P gradients and with a late temporal onset in NBs, trigger the type I amp;gt; 0 daughter proliferation switch and NB exit. Given the highly evolutionarily conserved expression of overlapping Hox homeotic genes in the CNS, our results point to a common mechanism for generating the CNS wedge.

Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Developmental Biology
Identifiers
urn:nbn:se:liu:diva-137604 (URN)10.1016/j.cub.2017.03.023 (DOI)000399986500023 ()28392108 (PubMedID)
Note

Funding Agencies|Swedish Research Council [621-2013-5258]; Knut and Alice Wallenberg Foundation [KAW2011.0165, KAW2012.0101]; Swedish Cancer Foundation [150663]

Available from: 2017-05-22 Created: 2017-05-22 Last updated: 2018-05-09
3. Evolutionarily conserved anterior expansion of the central nervous system promoted by a common PcG-Hox program
Open this publication in new window or tab >>Evolutionarily conserved anterior expansion of the central nervous system promoted by a common PcG-Hox program
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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
Keywords
Asymmetric division, Cell cycle, Combinatorial control, Evolution of the CNS, Lineage size, Nervous system development
National Category
Developmental Biology
Identifiers
urn:nbn:se:liu:diva-147741 (URN)10.1242/dev.160747 (DOI)000438944000010 ()29530878 (PubMedID)2-s2.0-85045513794 (Scopus ID)
Available from: 2018-05-09 Created: 2018-05-09 Last updated: 2018-12-10Bibliographically approved

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Yaghmaeian Salmani, Behzad

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