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Neuronal cell fate diversification controlled by sub-temporal action of Kruppel
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. University of Autonoma Madrid, Spain.
University of Autonoma Madrid, Spain.
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: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e19311e19311Article in journal (Refereed) Published
Abstract [en]

During Drosophila embryonic nervous system development, neuroblasts express a programmed cascade of five temporal transcription factors that govern the identity of cells generated at different time-points. However, these five temporal genes fall short of accounting for the many distinct cell types generated in large lineages. Here, we find that the late temporal gene castor sub-divides its large window in neuroblast 5-6 by simultaneously activating two cell fate determination cascades and a sub-temporal regulatory program. The sub-temporal program acts both upon itself and upon the determination cascades to diversify the castor window. Surprisingly, the early temporal gene Kruppel acts as one of the sub-temporal genes within the late castor window. Intriguingly, while the temporal gene castor activates the two determination cascades and the sub-temporal program, spatial cues controlling cell fate in the latter part of the 5-6 lineage exclusively act upon the determination cascades.

Place, publisher, year, edition, pages
eLife Sciences Publications Ltd. , 2016. Vol. 5, article id e19311e19311
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-132850DOI: 10.7554/eLife.19311ISI: 000386456200001PubMedID: 27740908OAI: oai:DiVA.org:liu-132850DiVA, id: diva2:1052421
Note

Funding Agencies|Svenska Forskningsradet Formas [621-2013-5258]; Cancerfonden [120531]; Knut och Alice Wallenbergs Stiftelse [KAW2011.0165]; Ministerio de Industria, Energia y Turismo [BFU2013-43858-P]

Available from: 2016-12-06 Created: 2016-11-30 Last updated: 2018-03-19
In thesis
1. Genetic Mechanisms during Terminal Cell Fate Specification in the Drosophila CNS
Open this publication in new window or tab >>Genetic Mechanisms during Terminal Cell Fate Specification in the Drosophila CNS
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Specification of the many unique neuronal subtypes found in the nervous system depends on spatiotemporal cues and terminal selector cascades, mostly acting in sequential combinatorial codes of transcription factors (TFs) to dictate cell fate. Out of 10,000 cells in the Drosophila embryonic ventral nerve cord (VNC), only 28 cells selectively express Nplp1. The Nplp1 neurons in the Drosophila VNC can be subdivided into the thoracic ventro-lateral Tv1 and the dorsal-medial dAp neurons. Nplp1 expression in both cell subtypes is activated by the same terminal selector cascade: col > ap/eya > dimm > Nplp1. However Tv1 and dAp neurons are generated by different neuronal progenitors (neuroblasts, NB), and depend on different upstream cues to activate the cell specification cascade. The Tv1 cells are generated by NB5-6T, and in these cells the Nplp1 terminal selector cascade is triggered by spatio-temporal input provided by Antp/hth/exd/lbe/cas. Our studies identified that NB4-3 gives rise to the dAp cells and that the Nplp1 terminal selector cascade in dAp cells is activated by Kr/pdm>grn. I demonstrated how two different spatio-temporal combinations can funnel on a shared downstream terminal selector cascade to determine a highly related cell fate, in different regions of the VNC. I tested this scenario at the molecular level, by identification of cisregulatory modules (CRMs) for the main factors involved in the Nplp1 terminal selector cascade. Intriguingly, I found that col is under control of two separate CRMs, which are controlled by either Antp/hth/exd/lbe/cas in the NB5-6T lineage, and Kr/pdm/grn in the NB4-3 lineage. In addition, CRISPR deletion of the endogenous col CRMs did not result in loss of Col and Nplp1, indicating that col might be under control of more, yet unidentified CRMs. Nplp1 is expressed in one out of four cells in the thoracic Apterous cluster (Ap cluster); the Tv1 cell. The allocation of the right cell fate to each of the four Ap cluster cells, is regulated by the sub-temporal cascade including the factors Sqz/Nab/Svp, acting downstream of the temporal factor Cas. The sub-temporal factors have a repressive action on Col and Dimm, and thus on the terminal selector cascade regulating Nplp1 expression in the Tv1  cell. We demonstrated that the late and Tv1 specific expression of the early temporal factor Kr suppresses Svp in the Tv1 cell and allows for the progression of the Nplp1 cell fate specification cascade. Hence, early temporal factors involved in temporal progression of neuronal progenitors, can be re-utilized late and postmitotically to specify cell fate. It is tempting to speculate that similar mechanisms act to generate similar cell fate in different regions of the CNS, as well as the issue of sub-temporal multitasking, are common features both in Drosophila and higher organisms.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. p. 61
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1550
National Category
Cell Biology Neurosciences Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-133225 (URN)10.3384/diss.diva-133225 (DOI)9789176856475 (ISBN)
Public defence
2017-02-02, Berzeliussalen, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-12-15 Created: 2016-12-15 Last updated: 2019-10-28Bibliographically approved

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