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Genetic Mechanisms during Terminal Cell Fate Specification in the Drosophila CNS
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
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: urn:nbn:se:liu:diva-133225DOI: 10.3384/diss.diva-133225ISBN: 9789176856475 (print)OAI: oai:DiVA.org:liu-133225DiVA, id: diva2:1056529
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: 2018-01-13Bibliographically approved
List of papers
1. Neuronal Cell Fate Specification by the Convergence of Different Spatiotemporal Cues on a Common Terminal Selector Cascade
Open this publication in new window or tab >>Neuronal Cell Fate Specification by the Convergence of Different Spatiotemporal Cues on a Common Terminal Selector Cascade
Show others...
2016 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 14, no 5, p. e1002450-Article in journal (Refereed) Published
Abstract [en]

Specification of the myriad of unique neuronal subtypes found in the nervous system depends upon spatiotemporal cues and terminal selector gene cascades, often acting in sequential combinatorial codes to determine final cell fate. However, a specific neuronal cell subtype can often be generated in different parts of the nervous system and at different stages, indicating that different spatiotemporal cues can converge on the same terminal selectors to thereby generate a similar cell fate. However, the regulatory mechanisms underlying such convergence are poorly understood. The Nplp1 neuropeptide neurons in the Drosophila ventral nerve cord can be subdivided into the thoracic-ventral Tv1 neurons and the dorsal-medial dAp neurons. The activation of Nplp1 in Tv1 and dAp neurons depends upon the same terminal selector cascade: colamp;gt;ap/eyaamp;gt;dimmamp;gt;Nplp1. However, Tv1 and dAp neurons are generated by different neural progenitors (neuroblasts) with different spatiotemporal appearance. Here, we find that the same terminal selector cascade is triggered by Kr/pdmamp;gt;grn in dAp neurons, but by Antp/hth/exd/lbe/cas in Tv1 neurons. Hence, two different spatiotemporal combinations can funnel into a common downstream terminal selector cascade to determine a highly related cell fate.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2016
National Category
Developmental Biology
Identifiers
urn:nbn:se:liu:diva-129501 (URN)10.1371/journal.pbio.1002450 (DOI)000376906100001 ()27276273 (PubMedID)
Note

Funding Agencies|Swedish Research Council (VR-NT) [621-2010-5214]; Wallenberg Foundation [KAW2012.0101]; Swedish Cancer Foundation [120531]; Spanish Ministerio de Economia y Competitividad [BFU2013-43858-P]

Available from: 2016-06-20 Created: 2016-06-20 Last updated: 2017-11-28
2. Neuronal cell fate diversification controlled by sub-temporal action of Kruppel
Open this publication in new window or tab >>Neuronal cell fate diversification controlled by sub-temporal action of Kruppel
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
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-132850 (URN)10.7554/eLife.19311 (DOI)000386456200001 ()27740908 (PubMedID)
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
3. Neuronal cell fate specification by the molecular convergence of different spatio-temporal cues on a common initiator terminal selector gene
Open this publication in new window or tab >>Neuronal cell fate specification by the molecular convergence of different spatio-temporal cues on a common initiator terminal selector gene
2017 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, p. 26Article in journal (Refereed) Published
Abstract [en]

The extensive genetic regulatory flows underlying specification of different neuronal subtypes are not well understood at the molecular level. The Nplp1 neuropeptide neurons in the developing Drosophila nerve cord belong to two sub-classes; Tv1 and dAp neurons, generated by two distinct progenitors. Nplp1 neurons are specified by spatial cues; the Hox homeotic network and GATA factor grn, and temporal cues; the hb -greater than Kr -greater than Pdm -greater than cas -greater than grh temporal cascade. These spatio-temporal cues combine into two distinct codes; one for Tv1 and one for dAp neurons that activate a common terminal selector feedforward cascade of col -greater than ap/eya -greater than dimm -greater than Nplp1. Here, we molecularly decode the specification of Nplp1 neurons, and find that the cis-regulatory organization of col functions as an integratory node for the different spatio-temporal combinatorial codes. These findings may provide a logical framework for addressing spatio-temporal control of neuronal sub-type specification in other systems. [ABSTRACT FROM AUTHOR]

Place, publisher, year, edition, pages
PLOS, 2017. p. 26
Keywords
Animal cells, Animal models, Animals, Arthropoda, Biochemistry, Biology and life sciences, Cell binding, Cell biology, Cell physiology, Cell staining, Cellular neuroscience, Cellular types, Developmental biology, DNA-binding proteins, Drosophila, Drosophila melanogaster, Embryology, Embryos, Experimental organism systems, Gene expression, Gene regulation, Genetics, Insects, Invertebrates, Model organisms, Neurons, Neuroscience, Organisms, Proteins, Regulatory proteins, Research and analysis methods, Research Article, Specimen preparation and treatment, Staining, Transcription factors
National Category
Developmental Biology
Identifiers
urn:nbn:se:liu:diva-136555 (URN)10.1371/journal.pgen.1006729 (DOI)000402549200037 ()28414802 (PubMedID)
Note

Funding agencies: Cancerfonden [140780]; Vetenskapsradet [621-20135258]; Knut och Alice Wallenbergs Stiftelse [KAW2011.0165]

Available from: 2017-04-19 Created: 2017-04-19 Last updated: 2017-06-26Bibliographically approved

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